Inhibitors of plasma kallikrein and uses thereof

ABSTRACT

The present invention provides compounds and compositions thereof which are useful as inhibitors of plasma kallikrein and which exhibit desirable characteristics for the same.

I. BACKGROUND OF THE INVENTION

Plasma Kallikrein (pKal) is a serine protease zymogen in blood that isconverted to its catalytically active form by coagulation factor XIIa,and contributes to the innate inflammatory response and intrinsiccascade of blood coagulation. The mechanisms that lead to the activationof this pathway in vivo include interactions with polyphosphatesreleased from activated platelets and deficiency of C1 inhibitor(C1-INH), the primary physiological inhibitor of pKal. pKal-mediatedcleavage of high-molecular weight kininogen generates the potentvasodilator and pro-inflammatory nonapeptide bradykinin (BK), whichactivates the bradykinin 2 receptor. Subsequent cleavage of BK bycarboxypeptidases generates des-Arg9-BK, which activates the B1receptor. Both B1 and B2 receptors are expressed by vascular, glial, andneuronal cell types, with the highest levels of retinal expressiondetected in the ganglion cell layer and inner and outer nuclear layers.Activation of B1 and B2 receptors causes vasodilation and increasesvascular permeability.

pKal is also associated with a number of disorders, such as hereditaryangioedema (HAE), an autosomal dominant disease characterized bypainful, unpredictable, recurrent attacks of inflammation affecting thehands, feet, face, abdomen, urogenital tract, and the larynx. Prevalencefor HAE is uncertain but is estimated to be approximately 1 case per50,000 persons without known differences among ethnic groups. HAE iscaused by deficient (Type I) or dysfunctional (Type II) levels ofC1-INH, which inhibits pKal, bradykinin, and other serine proteases inthe blood. Individuals with hereditary angioedema (HAE) are deficient inC1-INH and consequently undergo excessive bradykinin generation, whichin turn cause painful, debilitating, and potentially fatal swellingattacks. If left untreated, HAE can result in a mortality rate as highas 40% primarily due to upper airway obstruction.

II. SUMMARY OF THE INVENTION

The present disclosure is based on, at least in part, the development ofa number of compounds which bind to plasma kallikrein and effectivelyinhibit its activity. Accordingly, provided herein are compounds anduses thereof for targeting pKal and/or treating pKal-mediated diseasesand disorders.

In some embodiments, the present invention provides a compound ofFormula (I):

or a pharmaceutically acceptable salt thereof, wherein each of Cy^(A),Cy^(B), L, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, and R⁹ is defined and describedin classes and subclasses herein. In certain embodiments, the presentinvention provides compounds of Formulae (I)-(V), as defined anddescribed in classes and subclasses herein.

In some embodiments, the present invention also provides methods ofusing compounds of Formulae (I)-(V).

III. DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS A. Definitions

Compounds of this invention include those described generally above, andare further illustrated by the classes, subclasses, and speciesdisclosed herein. As used herein, the following definitions shall applyunless otherwise indicated. For purposes of this invention, the chemicalelements are identified in accordance with the Periodic Table of theElements, CAS version, Handbook of Chemistry and Physics, 75^(th) Ed.Additionally, general principles of organic chemistry are described in“Organic Chemistry”, Thomas Sorrell, University Science Books,Sausalito: 1999, and “March's Advanced Organic Chemistry”, 5^(th) Ed.,Ed.: Smith, M. B. and March, J., John Wiley & Sons, New York: 2001, theentire contents of which are hereby incorporated by reference.

The abbreviations used herein have their conventional meaning within thechemical and biological arts. The chemical structures and formulae setforth herein are constructed according to the standard rules of chemicalvalency known in the chemical arts.

The term “aliphatic” or “aliphatic group”, as used herein, means astraight-chain (i.e., unbranched) or branched, substituted orunsubstituted hydrocarbon chain that is completely saturated or thatcontains one or more units of unsaturation, or a monocyclic hydrocarbonor bicyclic hydrocarbon that is completely saturated or that containsone or more units of unsaturation, but which is not aromatic (alsoreferred to herein as “carbocyclyl,” “cycloaliphatic” or “cycloalkyl”),that has a single point of attachment to the rest of the molecule.Unless otherwise specified, aliphatic groups contain 1-6 aliphaticcarbon atoms. In some embodiments, aliphatic groups contain 1-5aliphatic carbon atoms. In some embodiments, aliphatic groups contain1-4 aliphatic carbon atoms. In some embodiments, aliphatic groupscontain 1-3 aliphatic carbon atoms, and in yet other embodiments,aliphatic groups contain 1-2 aliphatic carbon atoms. In someembodiments, “cycloaliphatic” (or “carbocyclyl” or “cycloalkyl”) refersto a monocyclic C₃-C₇ hydrocarbon that is completely saturated or thatcontains one or more units of unsaturation, but which is not aromatic,that has a single point of attachment to the rest of the molecule.Suitable aliphatic groups include, but are not limited to, linear orbranched, substituted or unsubstituted alkyl, alkenyl, alkynyl groupsand hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or(cycloalkyl)alkenyl.

The term “heteroatom” means one or more of oxygen, sulfur, nitrogen,phosphorus, or silicon (including, any oxidized form of nitrogen,sulfur, phosphorus, or silicon; the quaternized form of any basicnitrogen or; a substitutable nitrogen of a heterocyclic ring, forexample N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) orNR⁺ (as in N-substituted pyrrolidinyl)).

The term “unsaturated,” as used herein, means that a moiety has one ormore units of unsaturation.

The term “alkylene” refers to a bivalent alkyl group. An “alkylenechain” is a polymethylene group, i.e., —(CH₂)_(n)—, wherein n is apositive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3, from1 to 2, or from 2 to 3. A substituted alkylene chain is a polymethylenegroup in which one or more methylene hydrogen atoms are replaced with asubstituent. Suitable substituents include those described below for asubstituted aliphatic group.

The term “halogen” means F, Cl, Br, or I.

The term “aryl” refers to monocyclic and bicyclic ring systems having atotal of five to 10 ring members, wherein at least one ring in thesystem is aromatic and wherein each ring in the system contains three toseven ring members. The term “aryl” may be used interchangeably with theterm “aryl ring”. In some embodiments, an 8-10 membered bicyclic arylgroup is an optionally substituted naphthyl ring. In certain embodimentsof the present invention, “aryl” refers to an aromatic ring system whichincludes, but not limited to, phenyl, biphenyl, naphthyl, anthracyl andthe like, which may bear one or more substituents. Also included withinthe scope of the term “aryl,” as it is used herein, is a group in whichan aromatic ring is fused to one or more non-aromatic rings, such asindanyl, phthalimidyl, naphthimidyl, phenanthridinyl, ortetrahydronaphthyl, and the like.

The terms “heteroaryl” and “heteroar-” refer to groups having 5 to 10ring atoms, preferably 5, 6, or 9 ring atoms; having 6, 10, or 14 πelectrons shared in a cyclic array; and having, in addition to carbonatoms, from one to five heteroatoms. Heteroaryl groups include, withoutlimitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl,triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl,isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl,pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. Theterms “heteroaryl” and “heteroar-”, as used herein, also include groupsin which a heteroaromatic ring is fused to one or more aryl,cycloaliphatic, or heterocyclyl rings, where the radical or point ofattachment is on the heteroaromatic ring. Nonlimiting examples includeindolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl,indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl,cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl,carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl,tetrahydroquinolinyl, tetrahydroisoquinolinyl, andpyrido[2,3-b]-1,4-oxazin-3(4H)-one. A heteroaryl group may be mono- orbicyclic. The term “heteroaryl” may be used interchangeably with theterms “heteroaryl ring,” “heteroaryl group,” or “heteroaromatic,” any ofwhich terms include rings that are optionally substituted.

As used herein, the terms “heterocyclyl,” “heterocyclic radical,” and“heterocyclic ring” are used interchangeably and refer to a stable 5- to7-membered monocyclic or 7-10-membered bicyclic heterocyclic moiety thatis either saturated or partially unsaturated, and having, in addition tocarbon atoms, one or more, preferably one to four, heteroatoms, asdefined above. When used in this context in reference to a ring atom,the term “nitrogen” includes a substituted nitrogen. As an example, in asaturated or partially unsaturated ring having 0-3 heteroatoms selectedfrom oxygen, sulfur or nitrogen, the nitrogen may be N (as in3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or ⁺NR (as inN-substituted pyrrolidinyl).

A heterocyclic ring can be attached to its pendant group at anyheteroatom or carbon atom that results in a stable structure and any ofthe ring atoms can be optionally substituted. Examples of such saturatedor partially unsaturated heterocyclic radicals include, withoutlimitation, tetrahydrofuranyl, tetrahydrothiophenyl pyrrolidinyl,piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl,decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl,diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. Theterms “heterocyclyl,” “heterocyclyl ring,” “heterocyclic group,”“heterocyclic moiety,” and “heterocyclic radical,” are usedinterchangeably herein, and also include groups in which a heterocyclylring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings,such as indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, ortetrahydroquinolinyl, where the radical or point of attachment is on theheterocyclyl ring. A heterocyclyl group may be mono- or bicyclic. Theterm “heterocyclylalkyl” refers to an alkyl group substituted by aheterocyclyl, wherein the alkyl and heterocyclyl portions independentlyare optionally substituted.

As used herein, the term “partially unsaturated” refers to a ring moietythat includes at least one double or triple bond. The term “partiallyunsaturated” is intended to encompass rings having multiple sites ofunsaturation, but is not intended to include aryl or heteroarylmoieties, as herein defined.

As used herein and unless otherwise specified, the suffix “-ene” is usedto describe a bivalent group. Thus, any of the terms above can bemodified with the suffix “-ene” to describe a bivalent version of thatmoiety. For example, a bivalent carbocycle is “carbocycylene”, abivalent aryl ring is “arylene”, a bivalent benzene ring is “phenylene”,a bivalent heterocycle is “heterocyclylene”, a bivalent heteroaryl ringis “heteroarylene”, a bivalent alkyl chain is “alkylene”, a bivalentalkenyl chain is “alkenylene”, a bivalent alkynyl chain is “alkynylene”,and so forth.

As described herein, compounds of the invention may, when specified,contain “optionally substituted” moieties. In general, the term“substituted,” whether preceded by the term “optionally” or not, meansthat one or more hydrogens of the designated moiety are replaced with asuitable substituent. Unless otherwise indicated, an “optionallysubstituted” group may have a suitable substituent at each substitutableposition of the group, and when more than one position in any givenstructure may be substituted with more than one substituent selectedfrom a specified group, the substituent may be either the same ordifferent at every position. Combinations of substituents envisioned bythis invention are preferably those that result in the formation ofstable or chemically feasible compounds. The term “stable,” as usedherein, refers to compounds that are not substantially altered whensubjected to conditions to allow for their production, detection, and,in certain embodiments, their recovery, purification, and use for one ormore of the purposes disclosed herein.

Suitable monovalent substituents on a substitutable carbon atom of an“optionally substituted” group are independently halogen;—(CH₂)₀₋₄R^(∘); —(CH₂)₀₋₄OR^(∘); —O(CH₂)₀₋₄R^(∘), —O(CH₂)₀₋₄C(O)OR^(∘);—O(CH₂)₀₋₄OR^(∘); —(CH₂)₀₋₄CH(OR^(∘))₂; —(CH₂)₀₋₄SR^(∘); —(CH₂)₀₋₄Ph,which may be substituted with R^(∘); —(CH₂)₀₋₄O(CH₂)₀₋₁Ph which may besubstituted with R^(∘); —CH═CHPh, which may be substituted with R^(∘);—(CH₂)₀₋₄O(CH₂)₀₋₁-pyridyl which may be substituted with R^(∘); —NO₂;—CN; —N₃; —(CH₂)₀₋₄N(R^(∘))₂; —(CH₂)₀₋₄N(R^(∘))C(O)R^(∘);—N(R^(∘))C(S)R^(∘); —(CH₂)₀₋₄N(R^(∘))C(O)NR^(∘) ₂; —N(R^(∘))C(S)NR^(∘)₂; —(CH₂)₀₋₄N(R^(∘))C(O)OR^(∘); —N(R^(∘))N(R^(∘))C(O)R^(∘);—N(R^(∘))N(R^(∘))C(O)NR^(∘) ₂; —N(R^(∘))N(R^(∘))C(O)OR^(∘);—(CH₂)₀₋₄C(O)R^(∘); —C(S)R^(∘); —(CH₂)₀₋₄C(O)OR^(∘);—(CH₂)₀₋₄C(O)SR^(∘); —(CH₂)₀₋₄C(O)OSiR^(∘) ₃; —(CH₂)₀₋₄OC(O)R^(∘);—OC(O)(CH₂)₀₋₄SR^(∘), —SC(S)SR^(∘); —(CH₂)₀₋₄SC(O)R^(∘);—(CH₂)₀₋₄C(O)NR^(∘) ₂; —C(S)NR^(∘) ₂; —C(S)SR^(∘); —SC(S)SR^(∘),—(CH₂)₀₋₄OC(O)NR^(∘) ₂; —C(O)N(OR^(∘))R^(∘); —C(O)C(O)R^(∘);—C(O)CH₂C(O)R^(∘); —C(NOR^(∘))R^(∘); —(CH₂)₀₋₄SSR^(∘);—(CH₂)₀₋₄S(O)₂R^(∘); —(CH₂)₀₋₄S(O)₂OR^(∘); —(CH₂)₀₋₄OS(O)₂R^(∘);—S(O)₂NR^(∘) ₂; —(CH₂)₀₋₄S(O)R^(∘); —N(R^(∘))S(O)₂NR^(∘) ₂;—N(R^(∘))S(O)₂R^(∘); —N(OR^(∘))R^(∘); —C(NH)NR^(∘) ₂; —P(O)₂R^(∘);—P(O)R^(∘) ₂; —OP(O)R^(∘) ₂; —OP(O)(OR^(∘))₂; SiR^(∘) ₃; —(C₁₋₄ straightor branched alkylene)O—N(R^(∘))₂; or —(C₁₋₄ straight or branchedalkylene)C(O)O—N(R^(∘))₂, wherein each R^(∘) may be substituted asdefined below and is independently hydrogen, C₁₋₆ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, —CH₂-(5-6 membered heteroaryl ring), or a 5-6 memberedsaturated, partially unsaturated, or aryl ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or,notwithstanding the definition above, two independent occurrences ofR^(∘), taken together with their intervening atom(s), form a 3-12membered saturated, partially unsaturated, or aryl mono- or bicyclicring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur, which may be substituted as defined below.

Suitable monovalent substituents on R^(∘) (or the ring formed by takingtwo independent occurrences of R^(∘) together with their interveningatoms), are independently halogen, —(CH₂)₀₋₂R^(•), -(haloR^(•)),—(CH₂)₀₋₂OH, —(CH₂)₀₋₂OR^(•), —(CH₂)₀₋₂CH(OR^(•))₂; —O(haloR^(•)), —CN,—N₃, —(CH₂)₀₋₂C(O)R^(•), —(CH₂)₀₋₂C(O)OH, —(CH₂)₀₋₂C(O)OR^(•),—(CH₂)₀₋₂SR^(•), —(CH₂)₀₋₂SH, —(CH₂)₀₋₂NH₂, —(CH₂)₀₋₂NHR^(•),—(CH₂)₀₋₂NR^(•) ₂, —NO₂, —SiR^(•)3, —OSiR^(•)3, —C(O)SR^(•), —(C₁₋₄straight or branched alkylene)C(O)OR^(•), or —SSR^(•) wherein each R^(•)is unsubstituted or where preceded by “halo” is substituted only withone or more halogens, and is independently selected from C₁₋₄ aliphatic,—CH₂Ph, —O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partiallyunsaturated, or aryl ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur. Suitable divalent substituents on asaturated carbon atom of R^(∘) include ═O and ═S.

Suitable divalent substituents on a saturated carbon atom of an“optionally substituted” group include the following: ═O, ═S, ═NNR*₂,═NNHC(O)R*, ═NNHC(O)OR*, ═NNHS(O)₂R*, ═NR*, ═NOR*, —O(C(R*₂))₂₋₃O—, or—S(C(R*₂))₂₋₃S—, wherein each independent occurrence of R* is selectedfrom hydrogen, C₁₋₆ aliphatic which may be substituted as defined below,or an unsubstituted 5-6 membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur. Suitable divalent substituents that are bound tovicinal substitutable carbons of an “optionally substituted” groupinclude: —O(CR*₂)₂₋₃O—, wherein each independent occurrence of R* isselected from hydrogen, C₁₋₆ aliphatic which may be substituted asdefined below, or an unsubstituted 5-6-membered saturated, partiallyunsaturated, or aryl ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur.

Suitable substituents on the aliphatic group of R* include halogen,—R^(•), -(haloR^(•)), —OH, —OR^(•), —O(haloR^(•)), —CN, —C(O)OH,—C(O)OR^(•), —NH₂, —NHR^(•), —NR^(•) ₂, or —NO₂, wherein each R^(•) isunsubstituted or where preceded by “halo” is substituted only with oneor more halogens, and is independently C₁₋₄ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, or a 5-6 membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur.

Suitable substituents on a substitutable nitrogen of an “optionallysubstituted” group include —R^(†), —NR^(†) ₂, —C(O)R^(†), —C(O)OR^(†),—C(O)C(O)R^(†), —C(O)CH₂C(O)R^(†), —S(O)₂R^(†), —S(O)₂NR^(†) ₂,—C(S)NR^(†) ₂, —C(NH)NR^(†) ₂, or —N(R^(†))S(O)₂R^(†); wherein eachR^(†) is independently hydrogen, C₁₋₆ aliphatic which may be substitutedas defined below, unsubstituted —OPh, or an unsubstituted 5-6-memberedsaturated, partially unsaturated, or aryl ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or,notwithstanding the definition above, two independent occurrences ofR^(†), taken together with their intervening atom(s) form anunsubstituted 3-12 membered saturated, partially unsaturated, or arylmono- or bicyclic ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur.

Suitable substituents on the aliphatic group of R^(†) are independentlyhalogen, —R^(•), -(haloR^(•)), —OH, —OR^(•), —O(haloR^(•)), —CN,—C(O)OH, —C(O)OR^(•), —NH₂, —NHR^(•), —NR^(•) ₂, or —NO₂, wherein eachR^(•) is unsubstituted or where preceded by “halo” is substituted onlywith one or more halogens, and is independently C₁₋₄ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur.

As used herein, the term “pharmaceutically acceptable salt” refers tothose salts which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like, andare commensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well known in the art. For example, S. M. Berge etal., describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein byreference.

In certain embodiments, the neutral forms of the compounds areregenerated by contacting the salt with a base or acid and isolating theparent compound in the conventional manner. In some embodiments, theparent form of the compound differs from the various salt forms incertain physical properties, such as solubility in polar solvents.

Unless otherwise stated, structures depicted herein are also meant toinclude all isomeric (e.g., enantiomeric, diastereomeric, and geometric(or conformational)) forms of the structure; for example, the R and Sconfigurations for each asymmetric center, Z and E double bond isomers,and Z and E conformational isomers. Therefore, single stereochemicalisomers as well as enantiomeric, diastereomeric, and geometric (orconformational) mixtures of the present compounds are within the scopeof the invention. Unless otherwise stated, all tautomeric forms of thecompounds of the invention are within the scope of the invention.Additionally, unless otherwise stated, structures depicted herein arealso meant to include compounds that differ only in the presence of oneor more isotopically enriched atoms. For example, compounds having thepresent structures including the replacement of hydrogen by deuterium ortritium, or the replacement of a carbon by a ¹³C- or ¹⁴C-enriched carbonare within the scope of this invention. Such compounds are useful, forexample, as analytical tools, as probes in biological assays, or astherapeutic agents in accordance with the present invention.

The term “oxo,” as used herein, means an oxygen that is double bonded toa carbon atom, thereby forming a carbonyl.

The symbol “

”, except when used as a bond to depict unknown or mixedstereochemistry, denotes the point of attachment of a chemical moiety tothe remainder of a molecule or chemical formula.

The articles “a” and “an” are used herein to refer to one or to morethan one (i.e., to at least one) of the grammatical object of thearticle. By way of example, “an element” means one element or more thanone element.

A “dosing regimen” (or “therapeutic regimen”), as that term is usedherein, is a set of unit doses (typically more than one) that areadministered individually to a subject, typically separated by periodsof time. In some embodiments, a given therapeutic agent has arecommended dosing regimen, which may involve one or more doses. In someembodiments, a dosing regimen comprises a plurality of doses each ofwhich are separated from one another by a time period of the samelength; in some embodiments, a dosing regimen comprises a plurality ofdoses and at least two different time periods separating individualdoses.

As will be understood from context, a “reference” sample or subject isone that is sufficiently similar to a particular sample or subject ofinterest to permit a relevant comparison. In some embodiments,information about a reference sample is obtained simultaneously withinformation about a particular sample. In some embodiments, informationabout a reference sample is historical. In some embodiments, informationabout a reference sample is stored, for example in a computer-readablemedium. In some embodiments, comparison of a particular sample ofinterest with a reference sample establishes identity with, similarityto, or difference of the particular sample of interest relative to thereference.

As used herein, the term “sample” refers to a biological sample obtainedor derived from a source of interest, as described herein. In someembodiments, a source of interest comprises an organism, such as ananimal or human. In some embodiments, a biological sample comprisesbiological tissue or fluid. In some embodiments, a biological sample maybe or comprise bone marrow; blood, e.g., whole blood; blood cells;ascites; tissue or fine needle biopsy samples; cell-containing bodyfluids; free floating nucleic acids; sputum; saliva; urine;cerebrospinal fluid, peritoneal fluid; pleural fluid; feces; lymph;gynecological fluids; skin swabs; vaginal swabs; oral swabs; nasalswabs; washings or lavages such as a ductal lavages or broncheoalveolarlavages; aspirates; scrapings; bone marrow specimens; tissue biopsyspecimens; surgical specimens; feces, other body fluids, secretions,and/or excretions; and/or cells therefrom, etc. In some embodiments, abiological sample is or comprises cells obtained from a subject. In someembodiments, obtained cells are or include cells from a subject fromwhom the sample is obtained. In some embodiments, a sample is a “primarysample” obtained directly from a source of interest by any appropriatemeans. For example, in some embodiments, a primary biological sample isobtained by methods selected from the group consisting of biopsy (e.g.,fine needle aspiration or tissue biopsy), surgery, collection of bodyfluid (e.g., blood (e.g., whole blood), lymph, feces etc.), etc. In someembodiments, as will be clear from context, the term “sample” refers toa preparation that is obtained by processing (e.g., by removing one ormore components of and/or by adding one or more agents to) a primarysample. For example, filtering using a semi-permeable membrane. Such a“processed sample” may comprise, for example nucleic acids or proteinsextracted from a sample or obtained by subjecting a primary sample totechniques such as amplification or reverse transcription of mRNA,isolation and/or purification of certain components, etc.

As used herein, the phrase “therapeutic agent” refers to any agent thathas a therapeutic effect and/or elicits a desired biological and/orpharmacological effect, when administered to a subject.

As used herein, the term “therapeutically effective amount” refers to anamount of a therapeutic agent that confers a therapeutic effect on thetreated subject, at a reasonable benefit/risk ratio applicable to anymedical treatment. The therapeutic effect may be objective (i.e.,measurable by some test or marker) or subjective (i.e., subject gives anindication of or feels an effect). In particular, the “therapeuticallyeffective amount” refers to an amount of a therapeutic agent effectiveto treat, ameliorate, or prevent a desired disease or condition, or toexhibit a detectable therapeutic or preventative effect, such as byameliorating symptoms associated with the disease, preventing ordelaying the onset of the disease, and/or also lessening the severity orfrequency of symptoms of the disease. A therapeutically effective amountis commonly administered in a dosing regimen that may comprise multipleunit doses. For any particular therapeutic agent, a therapeuticallyeffective amount (and/or an appropriate unit dose within an effectivedosing regimen) may vary, for example, depending on route ofadministration, on combination with other pharmaceutical agents. Also,the specific therapeutically effective amount (and/or unit dose) for anyparticular subject may depend upon a variety of factors including thedisorder being treated and the severity of the disorder; the activity ofthe specific therapeutic agent employed; the specific compositionemployed; the age, body weight, general health, sex and diet of thesubject; the time of administration, route of administration, and/orrate of excretion or metabolism of the specific therapeutic agentemployed; the duration of the treatment; and like factors as is wellknown in the medical arts.

As used herein, the term “treatment” (also “treat” or “treating”) refersto any administration of a substance (e.g., provided compositions) thatpartially or completely alleviates, ameliorates, relives, inhibits,delays onset of, reduces severity of, and/or reduces incidence of one ormore symptoms, features, and/or causes of a particular disease,disorder, and/or condition. Such treatment may be of a subject who doesnot exhibit signs of the relevant disease, disorder and/or conditionand/or of a subject who exhibits only early signs of the disease,disorder, and/or condition. Alternatively or additionally, suchtreatment may be of a subject who exhibits one or more established signsof the relevant disease, disorder and/or condition. In some embodiments,treatment may be of a subject who has been diagnosed as suffering fromthe relevant disease, disorder, and/or condition. In some embodiments,treatment may be of a subject known to have one or more susceptibilityfactors that are statistically correlated with increased risk ofdevelopment of the relevant disease, disorder, and/or condition.

B. Compounds

In some embodiments, a provided compound is of Formula (I):

or a pharmaceutically acceptable salt thereof,wherein:

-   Cy^(A) is selected from 3- to 7-membered saturated or partially    unsaturated monocyclic heterocyclylene having 1-2 heteroatoms    selected from oxygen, nitrogen, or sulfur, 5- to 6-membered    heteroarylene having 1-4 heteroatoms selected from oxygen, nitrogen,    or sulfur, 7- to 10-membered saturated or partially unsaturated    bicyclic heterocyclylene having 1-4 heteroatoms selected from    oxygen, nitrogen, or sulfur, and 7- to 10-membered bicyclic    heteroarylene having 1-4 heteroatoms selected from oxygen, nitrogen,    or sulfur, wherein Cy^(A) is substituted with 0-4 R^(A) groups;-   each R^(A) is independently selected from halogen, —CN, —C(R)═N(R),    —C(O)R, —C(O)₂R, —C(O)N(R)₂, —NO₂, —N(R)—N(R)₂, —N(R)₂, —N(R)C(O)R,    —N(R)C(O)₂R, —N(R)C(O)N(R)₂, —N(R)S(O)₂R, —OR, —OC(O)R, —OC(O)N(R)₂,    —SR, —S(O)R, —S(O)₂R, —S(O)N(R)₂, —S(O)₂N(R)₂, or an optionally    substituted group selected from C₁₋₆ aliphatic, phenyl, 5- to    6-membered heteroaryl having 1-4 heteroatoms selected from oxygen,    nitrogen, or sulfur, 3- to 7-membered saturated or partially    unsaturated monocyclic carbocyclyl, and 3- to 7-membered saturated    or partially unsaturated monocyclic heterocyclyl having 1-2    heteroatoms selected from oxygen, nitrogen, or sulfur;-   Cy^(B) is selected from 3- to 7-membered saturated or partially    unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected    from oxygen, nitrogen, or sulfur, 5- to 6-membered heteroaryl having    1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 7- to    10-membered saturated or partially unsaturated bicyclic heterocyclyl    having 1-5 heteroatoms selected from oxygen, nitrogen, or sulfur,    and 7- to 10-membered bicyclic heteroaryl having 1-5 heteroatoms    selected from oxygen, nitrogen, or sulfur, wherein Cy^(B) is    substituted with 0-5 R^(B) groups;-   each R^(B) is independently selected from halogen, —CN, —C(R)═N(R),    —C(O)R, —C(O)₂R, —C(O)N(R)₂, —NO₂, —N(R)—N(R)₂, —N(R)₂, —N(R)C(O)R,    —N(R)C(O)₂R, —N(R)C(O)N(R)₂, —N(R)S(O)₂R, —OR, —OC(O)R, —OC(O)N(R)₂,    —SR, —S(O)R, —S(O)₂R, —S(O)N(R)₂, —S(O)₂N(R)₂, or an optionally    substituted group selected from C₁₋₆ aliphatic, phenyl, 5- to    6-membered heteroaryl having 1-4 heteroatoms selected from oxygen,    nitrogen, or sulfur, 3- to 7-membered saturated or partially    unsaturated monocyclic carbocyclyl, and 3- to 7-membered saturated    or partially unsaturated monocyclic heterocyclyl having 1-2    heteroatoms selected from oxygen, nitrogen, or sulfur;-   L is selected from -QC(R)₂—, —C(R)₂Q-, -QC(Q)-, —C(Q)Q-,    —C(R)₂QC(O)—, and —C(O)QC(R)₂—, wherein each Q is independently a    monovalent or divalent group as valency allows, selected from the    group consisting of O, N(R), or (S);-   R¹, R², R³, and R⁴ are independently selected from hydrogen and C₁₋₆    aliphatic;-   R⁵, R⁶, R⁷, R⁸, and R⁹ are independently selected from hydrogen,    halogen, —CN, —C(R)═N(R), —C(O)R, —C(O)₂R, —C(O)N(R)₂, —NO₂,    —N(R)—N(R)₂, —N(R)₂, —N(R)C(O)R, —N(R)C(O)₂R, —N(R)C(O)N(R)₂,    —N(R)S(O)₂R, —OR, —OC(O)R, —OC(O)N(R)₂, —SR, —S(O)R, —S(O)₂R,    —S(O)N(R)₂, —S(O)₂N(R)₂, or an optionally substituted group selected    from C₁₋₆ aliphatic, phenyl, 5- to 6-membered heteroaryl having 1-4    heteroatoms selected from oxygen, nitrogen, or sulfur, 3- to    7-membered saturated or partially unsaturated monocyclic    carbocyclyl, and 3- to 7-membered saturated or partially unsaturated    monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen,    nitrogen, or sulfur; and-   each R is independently hydrogen, —CN, or an optionally substituted    group selected from C₁₋₆ aliphatic, phenyl, 5- to 6-membered    heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or    sulfur, 3- to 7-membered saturated or partially unsaturated    monocyclic carbocyclyl, and 3- to 7-membered saturated or partially    unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected    from oxygen, nitrogen, or sulfur;-   or two R groups on the same carbon or nitrogen are taken together    with their intervening atoms to form a ring selected from 3- to    7-membered saturated or partially unsaturated monocyclic ring having    0-2 heteroatoms selected from oxygen, nitrogen, or sulfur, and 5- to    6-membered heteroaryl having 1-4 heteroatoms selected from oxygen,    nitrogen, or sulfur;-   with the proviso that the compound is other than    N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-2-((3-chloroquinolin-6-yl)methyl)isonicotinamide.

In some embodiments, a provided compound, or a pharmaceuticallyacceptable salt thereof, has a structure of Formula (I), with theproviso that Cy^(A) is a group other than pyridinediyl and the compoundis other thanN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-2-((3-chloroquinolin-6-yl)methyl)isonicotinamide.

In some embodiments, Cy^(A) is selected from 3- to 7-membered saturatedor partially unsaturated monocyclic heterocyclylene having 1-2heteroatoms selected from oxygen, nitrogen, or sulfur, 5- to 6-memberedheteroarylene having 1-4 heteroatoms selected from oxygen, nitrogen, orsulfur, 7- to 10-membered saturated or partially unsaturated bicyclicheterocyclylene having 1-4 heteroatoms selected from oxygen, nitrogen,or sulfur, and 7- to 10-membered bicyclic heteroarylene having 1-4heteroatoms selected from oxygen, nitrogen, or sulfur, wherein Cy^(A) issubstituted with 0-4 R^(A) groups.

In some embodiments, Cy^(A) is selected from 5- to 6-memberedheteroarylene having 1-4 heteroatoms selected from oxygen, nitrogen, orsulfur, and 7- to 10-membered bicyclic heteroarylene having 1-4heteroatoms selected from oxygen, nitrogen, or sulfur wherein Cy^(A) issubstituted with 0-4 R^(A) groups.

In some embodiments, Cy^(A) is a 5- to 6-membered heteroarylene having1-4 heteroatoms selected from oxygen, nitrogen, or sulfur.

In some embodiments, Cy^(A) is a 6-membered heteroarylene having 1-4heteroatoms selected from oxygen, nitrogen, or sulfur, wherein Cy^(A) issubstituted with 0-3 R^(A) groups. In some embodiments, Cy^(A) is a6-membered heteroarylene having 1 nitrogen, wherein Cy^(A) issubstituted with 0-3 R^(A) groups. In some embodiments, Cy^(A) ispyridinediyl. In some embodiments, Cy^(A) is selected from either:

wherein * represents to point of attachment to L.

In some embodiments, Cy^(A) is a 5-membered heteroarylene having 1-4heteroatoms selected from oxygen, nitrogen, or sulfur, wherein Cy^(A) issubstituted with 0-2 R^(A) groups. In some embodiments, Cy^(A) is apyrrolediyl substituted with 0-3 R^(A) groups. In some embodiments,Cy^(A) is a pyrazolediyl substituted with 0-2 R^(A) groups. In someembodiments, Cy^(A) is a triazolediyl substituted with 0-1 R^(A) groups.In some embodiments, Cy^(A) is a thiazolediyl substituted with 0-1 R^(A)groups. In some embodiments, Cy^(A) is an unsubstituted tetrazolediyl.In some embodiments, Cy^(A) is an unsubstituted oxadiazolediyl. In someembodiments, Cy^(A) is an unsubstituted thiadiazolediyl. In someembodiments, Cy^(A) is an imidazolediyl substituted with 0-2 R^(A)groups. In some embodiments, Cy^(A) is a oxazolediyl substituted with0-1 R^(A) groups. In some embodiments, Cy^(A) is a isoxazolediylsubstituted with 0-1 R^(A) groups.

In some embodiments, Cy^(A) is a 7- to 10-membered bicyclicheteroarylene having 1-4 heteroatoms selected from oxygen, nitrogen, orsulfur wherein Cy^(A) is substituted with 0-4 R^(A) groups. In someembodiments, Cy^(A) is a 9-membered bicyclic heteroarylene having 1-4heteroatoms selected from oxygen, nitrogen, or sulfur wherein Cy^(A) issubstituted with 0-4 R^(A) groups. In some embodiments, Cy^(A) is a9-membered bicyclic heteroarylene having 2 nitrogens wherein Cy^(A) issubstituted with 0-4 R^(A) groups. In some embodiments, Cy^(A) is apyrrolopyridinediyl substituted with 0-4 R^(A) groups.

In some embodiments, Cy^(A) is selected from the group consisting of:

wherein * represents to point of attachment to L.

In some embodiments, each R^(A) is independently selected from anoptionally substituted group selected from C₁₋₆ aliphatic, 3- to7-membered saturated or partially unsaturated monocyclic carbocyclyl,and 3- to 7-membered saturated or partially unsaturated monocyclicheterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, orsulfur.

In some embodiments, substituents on an optionally substituted R^(A)group are independently halogen, (CH₂)₀₋₄R^(∘), —(CH₂)₀₋₄OR^(∘); and—(CH₂)₀₋₄C(O)OR^(∘), wherein each R^(∘) is independently hydrogen, C₁₋₆aliphatic, or a 5-6 membered saturated, partially unsaturated, or arylring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur.

In some embodiments, a single instance of R^(A) is C₁₋₆ aliphaticsubstituted with halogen.

In some embodiments, a single instance of R^(A) is C₁₋₆ aliphaticsubstituted with —(CH₂)₀₋₄OR^(∘), wherein R^(∘) is hydrogen or C₁₋₆aliphatic.

In some embodiments, a single instance of R^(A) is C₁₋₆ aliphaticsubstituted with —(CH₂)₀₋₄C(O)OR^(∘), wherein R^(∘) is hydrogen or C₁₋₆aliphatic.

In some embodiments, a single instance of R^(A) is C₁₋₆ aliphatic issubstituted with 5-6 membered saturated, partially unsaturated, or arylring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur.

In some embodiments, a single instance of R^(A) is optionallysubstituted 3- to 7-membered saturated or partially unsaturatedmonocyclic carbocyclyl. In some embodiments, a single instance of R^(A)is optionally substituted cyclopropyl. In some embodiments, a singleinstance of R^(A) is cyclopropyl substituted with —(CH₂)₀₋₄C(O)OR^(∘)and R^(∘) is hydrogen or C₁₋₆ aliphatic.

In some embodiments, Cy^(B) is selected from phenyl, 7- to 10-memberedsaturated or partially unsaturated bicyclic heterocyclyl having 1-5heteroatoms selected from oxygen, nitrogen, or sulfur, and 7- to10-membered bicyclic heteroaryl having 1-5 heteroatoms selected fromoxygen, nitrogen, or sulfur, wherein Cy^(B) is substituted with 0-5R^(B) groups. In some embodiments, Cy^(B) is selected from phenyl and 7-to 10-membered bicyclic heteroaryl having 1-5 heteroatoms selected fromoxygen, nitrogen, or sulfur, wherein Cy^(B) is substituted with 0-5R^(B) groups.

In some embodiments, Cy^(B) is a 7- to 10-membered bicyclic heteroarylhaving 1-5 heteroatoms selected from oxygen, nitrogen, or sulfur,wherein Cy^(B) is substituted with 0-5 R^(B) groups.

In some embodiments, Cy^(B) is a 9-membered bicyclic heteroaryl having1-5 heteroatoms selected from oxygen, nitrogen, or sulfur, whereinCy^(B) is substituted with 0-5 R^(B) groups. In some embodiments, Cy^(B)is a 9-membered bicyclic heteroaryl having 2-3 nitrogens, wherein Cy^(B)is substituted with 0-5 R^(B) groups. In some embodiments, Cy^(B) is animidazopyridinyl group substituted with 0-5 R^(B) groups. In someembodiments, Cy^(B) is a pyrazolopyridinyl group substituted with 0-5R^(B) groups. In some embodiments, Cy^(B) is a pyrrolopyridinyl groupsubstituted with 0-4 R^(B) groups. In some embodiments, Cy^(B)triazolopyridinyl group substituted with 0-4 R^(B) groups. In someembodiments, Cy^(B) is a imidazopyrimidinyl group substituted with 0-4R^(B) groups. In some embodiments, Cy^(B) is a imidazopyridazinyl groupsubstituted with 0-4 R^(B) groups. In some embodiments, Cy^(B) is aindolizinyl group substituted with 0-5 R^(B) groups. In someembodiments, Cy^(B) is pyrazolopyrimidinyl group substituted with 0-4R^(B) groups.

In some embodiments, Cy^(B) is a indolyl group substituted with 0-5R^(B) groups. In some embodiments, Cy^(B) is a benzofuranyl groupsubstituted with 0-5 R^(B) groups. In some embodiments, Cy^(B) is apyrazolopyrimidinyl group substituted with 0-4 R^(B) groups. In someembodiments, Cy^(B) is a benzimidazolyl group substituted with 0-4 R^(B)groups. In some embodiments, Cy^(B) is a thienopyridinyl groupsubstituted with 0-4 R^(B) groups.

In some embodiments, Cy^(B) is selected from the group consisting of:

In some embodiments, Cy^(B) is a 10-membered bicyclic heteroaryl having1-5 heteroatoms selected from oxygen, nitrogen, or sulfur, whereinCy^(B) is substituted with 0-5 R^(B)groups. In some embodiments, Cy^(B)is a 10-membered bicyclic heteroaryl having 1 nitrogen, wherein Cy^(B)is substituted with 0-5 R^(B) groups. In some embodiments, Cy^(B) is aquinolonyl group substituted with 0-5 R^(B) groups. In some embodiments,Cy^(B) is a quinoxalinyl group substituted with 0-5 R^(B) groups. Insome embodiments, Cy^(B) is selected from the group consisting of:

In some embodiments, each R^(B) is independently selected from halogen,—CN, —C(O)R, —C(O)₂R, —N(R)₂, —OR, or an optionally substituted groupselected from C₁₋₆ aliphatic, 3- to 7-membered saturated or partiallyunsaturated monocyclic carbocyclyl, and 3- to 7-membered saturated orpartially unsaturated monocyclic heterocyclyl having 1-2 heteroatomsselected from oxygen, nitrogen, or sulfur, wherein each R isindependently hydrogen or C₁₋₆ aliphatic.

In some embodiments, substituents on an optionally substituted R^(B)group are independently selected from halogen, —(CH₂)₀₋₄OR^(∘),—O(CH₂)₀₋₄OR^(∘), —(CH₂)₀₋₄C(O)OR^(∘), and —(CH₂)₀₋₄N(R^(∘))₂ whereineach R^(∘) is independently hydrogen, C₁, aliphatic, or two independentoccurrences of R^(∘), taken together with their intervening atom(s),form an optionally substituted 3-12 membered saturated, partiallyunsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, which may befurther substituted.

In some embodiments, a single instance of R^(B) is halogen. In someembodiments, a single instance of R^(B) is —CN. In some embodiments, asingle instance of R^(B) is —C(O)R, wherein R hydrogen or C₁₋₆aliphatic. In some embodiments, a single instance of R^(B) is —C(O)₂R,wherein R hydrogen or C₁₋₆ aliphatic. In some embodiments, a singleinstance of R^(B) is —N(R)₂, wherein R hydrogen or C₁₋₆ aliphatic. Insome embodiments, a single instance of R^(B) is —OR, wherein R hydrogenor C₁₋₆ aliphatic.

In some embodiments, a single instance of R^(B) is C₁₋₆ aliphaticsubstituted with —(CH₂)₀₋₄OR^(∘), wherein R^(∘) is hydrogen or C₁₋₆aliphatic.

In some embodiments, a single instance of R^(B) is C₁₋₆ aliphaticsubstituted with —O(CH₂)₀₋₄OR^(∘), wherein R^(∘) is hydrogen or C₁₋₆aliphatic.

In some embodiments, a single instance of R^(B) is C₁₋₆ aliphaticsubstituted with —(CH₂)₀₋₄C(O)OR^(∘), wherein R^(∘) is hydrogen or C₁₋₆aliphatic.

In some embodiments, a single instance of R^(B) is optionallysubstituted 3- to 7-membered saturated or partially unsaturatedmonocyclic carbocyclyl. In some embodiments, a single instance of R^(B)is optionally substituted cyclopropyl. In some embodiments, a singleinstance of R^(B) is cyclopropyl is substituted with —(CH₂)₀₋₄OR^(∘) andR^(∘) is hydrogen or C₁. 6 aliphatic. In some embodiments, a singleinstance of R^(B) is cyclopropyl is substituted with —(CH₂)₀₋₄C(O)OR^(∘)and R^(∘) is hydrogen or C₁₋₆ aliphatic.

In some embodiments, a single instance of R^(B) is optionallysubstituted 3- to 7-membered saturated or partially unsaturatedmonocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen,nitrogen, or sulfur. In some embodiments, a single instance of R^(B) isoptionally substituted 4-membered saturated monocyclic heterocyclylhaving 1 oxygen. In some embodiments, a single instance of R^(B) is4-membered saturated monocyclic heterocyclyl having 1 oxygen, andsubstituted with —(CH₂)₀₋₄OR^(∘), wherein R^(∘) is hydrogen or C₁₋₆aliphatic.

In some embodiments, a single instance of R^(B) is C₁₋₆ aliphatic issubstituted with —(CH₂)₀₋₄N(R^(∘))₂, wherein two independent occurrencesof R^(∘), taken together with their intervening atom(s), form anoptionally substituted 3-12 membered saturated, partially unsaturated,or aryl mono- or bicyclic ring having 0-4 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur, which may be furthersubstituted. In some embodiments, a single instance of R^(B) is C₁₋₆aliphatic substituted with —(CH₂)₀₋₄N(R^(∘))₂, wherein two independentoccurrences of R^(∘), taken together with their intervening atom(s),form an optionally substituted 5-membered saturated monocyclic ringfurther substituted with ═O.

In some embodiments, L is selected from -QC(R)₂—, —C(R)₂Q-, —C(Q)Q-, or—C(R)₂QC(O)—, wherein Q is independently a monovalent or divalent groupas valency allows, selected from O, N(R), or (S). In some embodiments, Lis selected from -QC(R)₂—, —C(R)₂Q-, —C(Q)Q-, or —C(R)₂QC(O)—, wherein Qis independently a monovalent or divalent group as valency allows,selected from O or N(R). In some embodiments, L is selected from thegroup consisting of:

wherein # represents to point of attachment to Cy^(A).In some embodiments, L is —N(H)C(O)—. In some embodiments, L is—C(O)N(H)—.

In some embodiments, R⁵, R⁶, R⁷, R⁸, and R⁹ are independently selectedfrom hydrogen, halogen, —CN, —N(R)₂, —OR, or an optionally substitutedgroup selected from C₁₋₆ aliphatic, 3- to 7-membered saturated orpartially unsaturated monocyclic carbocyclyl, wherein each R isindependently hydrogen or C₁₋₆ aliphatic. In some embodiments, R⁵, R⁸,and R⁹ are hydrogen.

In some embodiments, R⁶ is selected from hydrogen or halogen. In someembodiments, R⁶ is hydrogen. In some embodiments R⁶ is halogen. In someembodiments R⁶ is F. In some embodiments R⁶ is Cl. In some embodimentsR⁶ is Br. In some embodiments R⁶ is I.

In some embodiments, R⁷ is selected from halogen or an optionallysubstituted C₁₋₆ aliphatic. In some embodiments R⁷ is halogen. In someembodiments R⁷ is F. In some embodiments R⁷ is Cl. In some embodimentsR⁷ is Br. In some embodiments R⁷ is I. In some embodiments, R⁷ isoptionally substituted C₁₋₆ aliphatic. In some embodiments, R⁷ isoptionally substituted C₁₋₅ aliphatic. In some embodiments, R⁷ isoptionally substituted C₁₋₄ aliphatic. In some embodiments, R⁷ isoptionally substituted C₁₋₃ aliphatic. In some embodiments, R⁷ isoptionally substituted C₁₋₂ aliphatic. In some embodiments, R⁷ isalkynyl.

In some embodiments, a provided compound is of Formula (II):

or a pharmaceutically acceptable salt thereof, wherein each of Cy^(A),Cy^(B), R¹, R², R⁶, and R⁷ is defined and described in classes andsubclasses herein;

-   with the proviso that the compound is other than    N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-2-((3-chloroquinolin-6-yl)methyl)isonicotinamide.

It will be understood that, unless otherwise specified or prohibited bythe foregoing definition of Formula (II), embodiments of variablesCy^(A), Cy^(B), R¹, R², R⁶, and R⁷ as defined above and described inclasses and subclasses herein, also apply to compounds of Formula (II),both singly and in combination.

In some embodiments, a provided compound, or a pharmaceuticallyacceptable salt thereof, has a structure of Formula (II), with theproviso that Cy^(A) is a group other than pyridinediyl and the compoundis other thanN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-2-((3-chloroquinolin-6yl)methyl)isonicotinamide.

In some embodiments, a provided compound, or a pharmaceuticallyacceptable salt thereof, has a structure of Formula (III-a), Formula(III-b), Formula (III-c), Formula (III-d),

wherein each of R^(A), Cy^(B), R¹, R², R⁶, and R⁷ is defined anddescribed in classes and subclasses herein.

It will be understood that, unless otherwise specified or prohibited bythe foregoing definition of Formula (III), embodiments of variablesR^(A), Cy^(B), R¹, R², R⁶, and R⁷ as defined above and described inclasses and subclasses herein, also apply to compounds of Formula(III-a), Formula (III-b), Formula (III-c), and Formula (III-d) bothsingly and in combination.

In some embodiments of Formulae (I), (II), (III-a), (III-b), (III-c),and (III-d), Cy^(B) is

wherein:

-   W¹, W², W³, and W⁴ are independently selected from carbon and    nitrogen;-   R¹⁰, R¹¹, R¹², R¹³, and R¹⁴ are each optionally present when    attached to a carbon atom, and if present correspond to an    occurrence of R^(B) independently selected from halogen, —CN,    —C(R)═N(R), —C(O)R, —C(O)₂R, —C(O)N(R)₂, —NO₂, —N(R)—N(R)₂, —N(R)₂,    —N(R)C(O)R, —N(R)C(O)₂R, —N(R)C(O)N(R)₂, —N(R)S(O)₂R, —OR, —OC(O)R,    —OC(O)N(R)₂, —SR, —S(O)R, —S(O)₂R, —S(O)N(R)₂, —S(O)₂N(R)₂, or an    optionally substituted group selected from C₁₋₆ aliphatic, phenyl,    5- to 6-membered heteroaryl having 1-4 heteroatoms selected from    oxygen, nitrogen, or sulfur, 3- to 7-membered saturated or partially    unsaturated monocyclic carbocyclyl, and 3- to 7-membered saturated    or partially unsaturated monocyclic heterocyclyl having 1-2    heteroatoms selected from oxygen, nitrogen, or sulfur; and-   each R is independently hydrogen, —CN, or an optionally substituted    group selected from C₁₋₆ aliphatic, phenyl, 5- to 6-membered    heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or    sulfur, 3- to 7-membered saturated or partially unsaturated    monocyclic carbocyclyl, and 3- to 7-membered saturated or partially    unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected    from oxygen, nitrogen, or sulfur;-   or two R groups on the same carbon or nitrogen are taken together    with their intervening atoms to form a ring selected from 3- to    7-membered saturated or partially unsaturated monocyclic ring having    0-2 heteroatoms selected from oxygen, nitrogen, or sulfur, and 5- to    6-membered heteroaryl having 1-4 heteroatoms selected from oxygen,    nitrogen, or sulfur.

In some embodiments, W¹ is nitrogen and W², W³ and W⁴ are carbon. Insome embodiments, W² is nitrogen and W¹, W³ and W⁴ are carbon. In someembodiments, W² and W³ are nitrogen and W¹ and W⁴ are carbon. In someembodiments, W² and W⁴ are nitrogen and W¹ and W³ are carbon.

In some embodiments of Formulae (I), (II), (III-a), (III-b), (III-c),and (III-d), Cy^(B) is

wherein:

-   W² is selected from carbon, nitrogen, oxygen, and sulfur;-   W¹, W³, and W⁴ are independently selected from carbon and nitrogen;-   R¹⁰, R¹¹, R¹², R¹³, and R¹⁴ are each optionally present when    attached to a carbon atom, and if present correspond to an    occurrence of R^(B) independently selected from halogen, —CN,    —C(R)═N(R), —C(O)R, —C(O)₂R, —C(O)N(R)₂, —NO₂, —N(R)—N(R)₂, —N(R)₂,    —N(R)C(O)R, —N(R)C(O)₂R, —N(R)C(O)N(R)₂, —N(R)S(O)₂R, —OR, —OC(O)R,    —OC(O)N(R)₂, —SR, —S(O)R, —S(O)₂R, —S(O)N(R)₂, —S(O)₂N(R)₂, or an    optionally substituted group selected from C₁₋₆ aliphatic, phenyl,    5- to 6-membered heteroaryl having 1-4 heteroatoms selected from    oxygen, nitrogen, or sulfur, 3- to 7-membered saturated or partially    unsaturated monocyclic carbocyclyl, and 3- to 7-membered saturated    or partially unsaturated monocyclic heterocyclyl having 1-2    heteroatoms selected from oxygen, nitrogen, or sulfur; and-   each R is independently hydrogen, —CN, or an optionally substituted    group selected from C₁₋₆ aliphatic, phenyl, 5- to 6-membered    heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or    sulfur, 3- to 7-membered saturated or partially unsaturated    monocyclic carbocyclyl, and 3- to 7-membered saturated or partially    unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected    from oxygen, nitrogen, or sulfur;-   or two R groups on the same carbon or nitrogen are taken together    with their intervening atoms to form a ring selected from 3- to    7-membered saturated or partially unsaturated monocyclic ring having    0-2 heteroatoms selected from oxygen, nitrogen, or sulfur, and 5- to    6-membered heteroaryl having 1-4 heteroatoms selected from oxygen,    nitrogen, or sulfur.

In some embodiments, a provided compound is of Formula (IV):

or a pharmaceutically acceptable salt thereof,wherein:

-   Cy^(A) is a 5-membered heteroarylene having 1-4 heteroatoms selected    from oxygen or nitrogen, wherein Cy^(A) is substituted with 0-3    R^(A) groups;-   each R^(A) is independently selected from halogen, —CN, —C(R)═N(R),    —C(O)R, —C(O)₂R, —C(O)N(R)₂, —NO₂, —N(R)—N(R)₂, —N(R)₂, —N(R)C(O)R,    —N(R)C(O)₂R, —N(R)C(O)N(R)₂, —N(R)S(O)₂R, —OR, —OC(O)R, —OC(O)N(R)₂,    —SR, —S(O)R, —S(O)₂R, —S(O)N(R)₂, —S(O)₂N(R)₂, or an optionally    substituted group selected from C₁₋₆ aliphatic, phenyl, 5- to    6-membered heteroaryl having 1-4 heteroatoms selected from oxygen,    nitrogen, or sulfur, 3- to 7-membered saturated or partially    unsaturated monocyclic carbocyclyl, and 3- to 7-membered saturated    or partially unsaturated monocyclic heterocyclyl having 1-2    heteroatoms selected from oxygen, nitrogen, or sulfur;-   L is selected from —NC(O)— and —C(O)N—;-   R⁶, R, and R⁹ are independently selected from hydrogen, halogen,    —CN, —C(R)═N(R), —C(O)R, —C(O)₂R, —C(O)N(R)₂, —NO₂, —N(R)—N(R)₂,    —N(R)₂, —N(R)C(O)R, —N(R)C(O)₂R, —N(R)C(O)N(R)₂, —N(R)S(O)₂R, —OR,    —OC(O)R, —OC(O)N(R)₂, —SR, —S(O)R, —S(O)₂R, —S(O)N(R)₂, —S(O)₂N(R)₂,    or an optionally substituted group selected from C₁₋₆ aliphatic,    phenyl, 5- to 6-membered heteroaryl having 1-4 heteroatoms selected    from oxygen, nitrogen, or sulfur, 3- to 7-membered saturated or    partially unsaturated monocyclic carbocyclyl, and 3- to 7-membered    saturated or partially unsaturated monocyclic heterocyclyl having    1-2 heteroatoms selected from oxygen, nitrogen, or sulfur;-   R⁷ is —F, —Cl, or —Br;-   W⁴ is carbon or nitrogen;-   R¹⁰ and R¹¹ are each optionally present, and if present are    independently selected from halogen, —CN, —C(R)═N(R), —C(O)R,    —C(O)₂R, —C(O)N(R)₂, —NO₂, —N(R)—N(R)₂, —N(R)₂, —N(R)C(O)R,    —N(R)C(O)₂R, —N(R)C(O)N(R)₂, —N(R)S(O)₂R, —OR, —OC(O)R, —OC(O)N(R)₂,    —SR, —S(O)R, —S(O)₂R, —S(O)N(R)₂, —S(O)₂N(R)₂, or an optionally    substituted group selected from C₁₋₆ aliphatic, phenyl, 5- to    6-membered heteroaryl having 1-4 heteroatoms selected from oxygen,    nitrogen, or sulfur, 3- to 7-membered saturated or partially    unsaturated monocyclic carbocyclyl, and 3- to 7-membered saturated    or partially unsaturated monocyclic heterocyclyl having 1-2    heteroatoms selected from oxygen, nitrogen, or sulfur;-   R¹³ is selected from halogen, —CN, —C(R)═N(R), —C(O)R, —C(O)₂R,    —C(O)N(R)₂, —NO₂, —N(R)—N(R)₂, —N(R)₂, —N(R)C(O)R, —N(R)C(O)₂R,    —N(R)C(O)N(R)₂, —N(R)S(O)₂R, —OR, —OC(O)R, —OC(O)N(R)₂, —SR, —S(O)R,    —S(O)₂R, —S(O)N(R)₂, —S(O)₂N(R)₂, or an optionally substituted group    selected from C₂₋₆ aliphatic, phenyl, 5- to 6-membered heteroaryl    having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 3-    to 7-membered saturated or partially unsaturated monocyclic    carbocyclyl, and 3- to 7-membered saturated or partially unsaturated    monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen,    nitrogen, or sulfur;-   R¹⁴ is optionally present, and if present and is selected from    halogen, —CN, —C(R)═N(R), —C(O)R, —C(O)₂R, —C(O)N(R)₂, —NO₂,    —N(R)—N(R)₂, —N(R)C(O)R, —N(R)C(O)₂R, —N(R)C(O)N(R)₂, —N(R)S(O)₂R,    —OC(O)R, —OC(O)N(R)₂, —SR, —S(O)R, —S(O)₂R, —S(O)N(R)₂, —S(O)₂N(R)₂,    or an optionally substituted group selected from C₃₋₆ aliphatic,    phenyl, 5- to 6-membered heteroaryl having 1-4 heteroatoms selected    from oxygen, nitrogen, or sulfur, 3- to 7-membered saturated or    partially unsaturated monocyclic carbocyclyl, and 3- to 7-membered    saturated or partially unsaturated monocyclic heterocyclyl having    1-2 heteroatoms selected from oxygen, nitrogen, or sulfur; and-   each R is independently hydrogen, —CN, or an optionally substituted    group selected from C₁₋₆ aliphatic, phenyl, 5- to 6-membered    heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or    sulfur, 3- to 7-membered saturated or partially unsaturated    monocyclic carbocyclyl, and 3- to 7-membered saturated or partially    unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected    from oxygen, nitrogen, or sulfur;-   or two R groups on the same carbon or nitrogen are taken together    with their intervening atoms to form a ring selected from 3- to    7-membered saturated or partially unsaturated monocyclic ring having    0-2 heteroatoms selected from oxygen, nitrogen, or sulfur, and 5- to    6-membered heteroaryl having 1-4 heteroatoms selected from oxygen,    nitrogen, or sulfur.

In some embodiments, Cy^(A) is a 5-membered heteroarylene having 1-4heteroatoms selected from oxygen or nitrogen. In some embodiments,Cy^(A) is a 5-membered heteroarylene having 1-4 nitrogens. In someembodiments, Cy^(A) is a 5-membered heteroarylene having 1-4 nitrogens,wherein when Cy^(A) comprises 3 nitrogens, it is not a a1,2,4-triazolediyl. In some embodiments, Cy^(A) is a 5-memberedheteroarylene having 1-3 nitrogens. In some embodiments, Cy^(A) is a5-membered heteroarylene having 1-2 nitrogens. In some embodiments,Cy^(A) is a 5-membered heteroarylene having 1 nitrogen. In someembodiments, Cy^(A) is a 5-membered heteroarylene having 2 nitrogens. Insome embodiments, Cy^(A) is a 5-membered heteroarylene having 3nitrogens. In some embodiments, Cy^(A) is a 5-membered heteroarylenehaving 4 nitrogens.

In some embodiments, Cy^(A) is selected from the group consisting of:

wherein * represents to point of attachment to L.

In some embodiments, W⁴ is carbon. In some embodiments W⁴ is nitrogen.

In some embodiments, R¹¹ is optionally present, and if present isindependently selected from halogen, —CN, —C(R)═N(R), —C(O)R,—C(O)N(R)₂, —NO₂, —N(R)—N(R)₂, —N(R)₂, —N(R)C(O)R, —N(R)C(O)₂R,—N(R)C(O)N(R)₂, —N(R)S(O)₂R, —OR, —OC(O)R, —OC(O)N(R)₂, —SR, —S(O)R,—S(O)₂R, —S(O)N(R)₂, —S(O)₂N(R)₂, or an optionally substituted groupselected from C₁₋₆ aliphatic, phenyl, 5- to 6-membered heteroaryl having1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 3- to7-membered saturated or partially unsaturated monocyclic carbocyclyl,and 3- to 7-membered saturated or partially unsaturated monocyclicheterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, orsulfur.

In some embodiments, R¹³ is selected from —CN, —C(R)═N(R), —C(O)R,—C(O)₂R, —C(O)N(R)₂, —NO₂, —N(R)—N(R)₂, —N(R)₂, —N(R)C(O)R, —N(R)C(O)₂R,—N(R)C(O)N(R)₂, —N(R)S(O)₂R, —OR, —OC(O)R, —OC(O)N(R)₂, —SR, —S(O)R,—S(O)₂R, —S(O)N(R)₂, —S(O)₂N(R)₂, or an optionally substituted groupselected from phenyl, 5- to 6-membered heteroaryl having 1-4 heteroatomsselected from oxygen, nitrogen, or sulfur, 3- to 7-membered saturated orpartially unsaturated monocyclic carbocyclyl, and 3- to 7-memberedsaturated or partially unsaturated monocyclic heterocyclyl having 1-2heteroatoms selected from oxygen, nitrogen, or sulfur.

In some embodiments, R¹¹ is selected from halogen, optionallysubstituted C₁₋₆ aliphatic, and optionally substituted 3- to 7-memberedsaturated or partially unsaturated monocyclic carbocyclyl.

In some embodiments, R¹¹ is halogen. In some embodiments, R¹¹ is —F. Insome embodiments, R¹¹ is —Cl. In some embodiments, R¹¹ is —Br. In someembodiments, R¹¹ is —I.

In some embodiments, R¹¹ is optionally substituted C₁₋₆ aliphatic. Insome embodiments, R¹¹ is optionally substituted C₁₋₅ aliphatic. In someembodiments, R¹¹ is optionally substituted C₁₋₄ aliphatic. In someembodiments, R¹¹ is optionally substituted C₁₋₃ aliphatic. In someembodiments, R¹¹ is optionally substituted C₁₋₂ aliphatic.

In some embodiments, R¹¹ is an optionally substituted 3- to 7-memberedsaturated or partially unsaturated monocyclic carbocyclyl. In someembodiments, R¹¹ is an optionally substituted 3- or 5-7-memberedsaturated or partially unsaturated monocyclic carbocyclyl. In someembodiments, R¹¹ is an optionally substituted 7-membered saturated orpartially unsaturated monocyclic carbocyclyl. In some embodiments, R¹¹is an optionally substituted 6-membered saturated or partiallyunsaturated monocyclic carbocyclyl. In some embodiments, R¹³ is anoptionally substituted 5-membered saturated or partially unsaturatedmonocyclic carbocyclyl. In some embodiments, R¹¹ is an optionallysubstituted 4-membered saturated or partially unsaturated monocycliccarbocyclyl. In some embodiments, R¹¹ is an optionally substituted3-membered saturated or partially unsaturated monocyclic carbocyclyl. Insome embodiments, R¹¹ is an optionally substituted cyclopropyl.

In some embodiments, a provided compound is of Formula (V):

or a pharmaceutically acceptable salt thereof,wherein:

-   Cy^(A) is a 5-membered heteroarylene having 1-4 nitrogens, wherein    when Cy^(A) comprises 3 nitrogens, it is not

-   L is selected from —NC(O)— and —C(O)N—;-   R⁶, R, and R⁹ are independently selected from hydrogen, halogen,    —CN, —C(R)═N(R), —C(O)R, —C(O)₂R, —C(O)N(R)₂, —NO₂, —N(R)—N(R)₂,    —N(R)₂, —N(R)C(O)R, —N(R)C(O)₂R, —N(R)C(O)N(R)₂, —N(R)S(O)₂R, —OR,    —OC(O)R, —OC(O)N(R)₂, —SR, —S(O)R, —S(O)₂R, —S(O)N(R)₂, —S(O)₂N(R)₂,    or an optionally substituted group selected from C₁₋₆ aliphatic,    phenyl, 5- to 6-membered heteroaryl having 1-4 heteroatoms selected    from oxygen, nitrogen, or sulfur, 3- to 7-membered saturated or    partially unsaturated monocyclic carbocyclyl, and 3- to 7-membered    saturated or partially unsaturated monocyclic heterocyclyl having    1-2 heteroatoms selected from oxygen, nitrogen, or sulfur;-   R⁷ is —F, —Cl, or —Br;-   R¹⁰ is optionally present, and if present is selected from halogen,    —CN, —C(R)═N(R), —C(O)R, —C(O)₂R, —C(O)N(R)₂, —NO₂, —N(R)—N(R)₂,    —N(R)₂, —N(R)C(O)R, —N(R)C(O)₂R, —N(R)C(O)N(R)₂, —N(R)S(O)₂R, —OR,    —OC(O)R, —OC(O)N(R)₂, —SR, —S(O)R, —S(O)₂R, —S(O)N(R)₂, —S(O)₂N(R)₂,    or an optionally substituted group selected from C₁₋₆ aliphatic,    phenyl, 5- to 6-membered heteroaryl having 1-4 heteroatoms selected    from oxygen, nitrogen, or sulfur, 3- to 7-membered saturated or    partially unsaturated monocyclic carbocyclyl, and 3- to 7-membered    saturated or partially unsaturated monocyclic heterocyclyl having    1-2 heteroatoms selected from oxygen, nitrogen, or sulfur;-   R¹¹ is optionally present, and if present is selected from halogen,    —CN, —C(R)═N(R), —C(O)R, —C(O)N(R)₂, —NO₂, —N(R)—N(R)₂, —N(R)₂,    —N(R)C(O)R, —N(R)C(O)₂R, —N(R)C(O)N(R)₂, —N(R)S(O)₂R, —OR, —OC(O)R,    —OC(O)N(R)₂, —SR, —S(O)R, —S(O)₂R, —S(O)N(R)₂, —S(O)₂N(R)₂, or an    optionally substituted group selected from C₁₋₆ aliphatic, phenyl,    5- to 6-membered heteroaryl having 1-4 heteroatoms selected from    oxygen, nitrogen, or sulfur, 3- to 7-membered saturated or partially    unsaturated monocyclic carbocyclyl, and 3- to 7-membered saturated    or partially unsaturated monocyclic heterocyclyl having 1-2    heteroatoms selected from oxygen, nitrogen, or sulfur;-   R¹³ is selected from —CN, —C(R)═N(R), —C(O)R, —C(O)₂R, —C(O)N(R)₂,    —NO₂, —N(R)—N(R)₂, —N(R)₂, —N(R)C(O)R, —N(R)C(O)₂R, —N(R)C(O)N(R)₂,    —N(R)S(O)₂R, —OR, —OC(O)R, —OC(O)N(R)₂, —SR, —S(O)R, —S(O)₂R,    —S(O)N(R)₂, —S(O)₂N(R)₂, or an optionally substituted group selected    from phenyl, 5- to 6-membered heteroaryl having 1-4 heteroatoms    selected from oxygen, nitrogen, or sulfur, 3- or 5-7-membered    saturated or partially unsaturated monocyclic carbocyclyl, and 3- to    7-membered saturated or partially unsaturated monocyclic    heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen,    or sulfur;-   R¹⁴ is optionally present, and if present and is selected from    halogen, —CN, —C(R)═N(R), —C(O)R, —C(O)₂R, —C(O)N(R)₂, —NO₂,    —N(R)—N(R)₂, —N(R)C(O)R, —N(R)C(O)₂R, —N(R)C(O)N(R)₂, —N(R)S(O)₂R,    —OC(O)R, —OC(O)N(R)₂, —SR, —S(O)R, —S(O)₂R, —S(O)N(R)₂, —S(O)₂N(R)₂,    or an optionally substituted group selected from C₃₋₆ aliphatic,    phenyl, 5- to 6-membered heteroaryl having 1-4 heteroatoms selected    from oxygen, nitrogen, or sulfur, 3- to 7-membered saturated or    partially unsaturated monocyclic carbocyclyl, and 3- to 7-membered    saturated or partially unsaturated monocyclic heterocyclyl having    1-2 heteroatoms selected from oxygen, nitrogen, or sulfur; and-   each R is independently hydrogen, —CN, or an optionally substituted    group selected from C₁₋₆ aliphatic, phenyl, 5- to 6-membered    heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or    sulfur, 3- to 7-membered saturated or partially unsaturated    monocyclic carbocyclyl, and 3- to 7-membered saturated or partially    unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected    from oxygen, nitrogen, or sulfur;-   or two R groups on the same carbon or nitrogen are taken together    with their intervening atoms to form a ring selected from 3- to    7-membered saturated or partially unsaturated monocyclic ring having    0-2 heteroatoms selected from oxygen, nitrogen, or sulfur, and 5- to    6-membered heteroaryl having 1-4 heteroatoms selected from oxygen,    nitrogen, or sulfur.

In some embodiments, a provided compound is selected from the groupconsisting ofN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((3-chloroquinolin-6-yl)methyl)-1H-pyrazole-4-carboxamide,N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide,N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-2-((3-chloroquinolin-6-yl)methyl)isonicotinamide,1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-((7-methylimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide,N-((7-bromoimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide,N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide,1-((6-chloro-5-methylimidazo[1,2-a]pyridin-2-yl)methyl)-N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide,N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-isopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide,N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((5-methylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide,N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-(1-methylcyclopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide,N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methyl)-1H-pyrazole-4-carboxamide,1-((7-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-((6-methoxyimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide,N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-5-methylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide,N-((7-bromoimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-5-methylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide,N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methyl)-1H-pyrazole-4-carboxamide,N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-7-methylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide,N-((7-bromoimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-7-methylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide,N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide,N-((7-bromoimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide,N-((7-bromoimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-7-fluoroimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide,N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-7-fluoroimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide,N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((5-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide,1-((5-chloro-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide,1-((7-chloro-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide,N-((7-bromoimidazo[1,5-a]pyridin-1-yl)methyl)-1-((7-chloro-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide,N-((7-bromoimidazo[1,5-a]pyridin-1-yl)methyl)-1-((5,6-dimethylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide,1-((5-bromoimidazo[1,2-a]pyridin-2-yl)methyl)-N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide,1-((6-bromo-7-methylimidazo[1,2-a]pyridin-2-yl)methyl)-N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide,N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide,N-((7-bromoimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide,N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-3-(methoxymethyl)-1H-pyrazole-4-carboxamide,N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-5-(methoxymethyl)-1H-pyrazole-4-carboxamide,N-((7,8-dichloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-methylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide,1-((6-chloro-5-ethylimidazo[1,2-a]pyridin-2-yl)methyl)-N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide,N-((7-chloro-8-methylimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-methylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide,1-((6-bromo-7-chloroimidazo[1,2-a]pyridin-2-yl)methyl)-N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide,1-((6-bromo-7-chloroimidazo[1,2-a]pyridin-2-yl)methyl)-N-((7-bromoimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide,N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-2-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)thiazole-5-carboxamide,1-((6-bromo-5-chloroimidazo[1,2-a]pyridin-2-yl)methyl)-N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide,1-((6-bromo-5-chloroimidazo[1,2-a]pyridin-2-yl)methyl)-N-((7-bromoimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide,N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((7-(2,2-dimethylcyclopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide,N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((7-(2-methylprop-1-en-1-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide,N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-(2-methylcyclopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide,N-((7-bromoimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-(2-methylcyclopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide,1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-((7-iodoimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide,N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((5-ethylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide,(Z)—N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-(prop-1-en-1-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide,1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-((7-cyclopropylimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide,N-((7-bromoimidazo[1,5-a]pyridin-1-yl)methyl)-1-((7-(2,2-dimethylcyclopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide,N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((5-cyclopropylpyrazolo[1,5-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide,N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-5-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1,3,4-oxadiazole-2-carboxamide,N-((7-bromoimidazo[1,5-a]pyridin-1-yl)methyl)-5-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1,3,4-oxadiazole-2-carboxamide,N-((6-aminoimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide,N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((5-cyanoimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide,N-((7-bromoimidazo[1,5-a]pyridin-1-yl)methyl)-1-((5-cyanoimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide,N-((7-bromoimidazo[1,5-a]pyridin-1-yl)methyl)-1-((5-cyclopropylpyrazolo[1,5-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide,N-((7-bromoimidazo[1,5-a]pyridin-1-yl)methyl)-1-((5-chloro-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide,N-((5-amino-7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-methylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide,N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-5-fluoroimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide,N-((7-bromoimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-5-fluoroimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide,N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclobutylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide,N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((5-(hydroxymethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide,N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((5-methoxyimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide,N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-methylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide,methyl3-(4-(((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazol-3-yl)propanoate,1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-((7-ethynylimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide,1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-((7-ethylimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide,N-((7-bromoimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methyl)-1H-pyrazole-4-carboxamide,N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-(imidazo[1,2-a]pyridin-2-ylmethyl)-1H-pyrazole-4-carboxamide,N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-5-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1,3,4-thiadiazole-2-carboxamide,ethyl2-((4-(((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-pyrazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-carboxylate,2-((4-(((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-pyrazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-carboxylicacid,3-(4-(((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazol-3-yl)propanoicacid,N-(1-(7-bromoimidazo[1,5-a]pyridin-1-yl)ethyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide,N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(hydroxymethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide,N-((7-bromoimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyrimidin-2-yl)methyl)-1H-pyrazole-4-carboxamide,N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((5-(methylamino)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide,N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-3-cyclopropyl-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide,N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-5-ethynylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide,N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide,methyl2-(2-((4-(((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-pyrazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)acetate,methyl3-(4-(((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazol-5-yl)propanoate,N-((7-bromo-3-(difluoromethyl)imidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide,N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-1H-pyrrolo[3,2-b]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide,N-((7-bromoimidazo[1,5-a]pyridin-1-yl)methyl)-3-cyclopropyl-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide,2-(2-((4-(((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-pyrazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)aceticacid,N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(hydroxyethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide,1-((5-amino-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide,1-((5-amino-8-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide,N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl-d2)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide,methyl2-((4-(((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-pyrazol-1-yl)methyl)imidazo[1,2-a]pyridine-6-carboxylate,N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((8-cyano-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide,ethyl3-(4-(((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazol-3-yl)propanoate,N-(2-(7-chloroimidazo[1,5-a]pyridin-1-yl)ethyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide,N-((7-bromoimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-3-(difluoromethyl)-1H-pyrazole-4-carboxamide,2-((4-(((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-pyrazol-1-yl)methyl)imidazo[1,2-a]pyridine-6-carboxylicacid,N-((7-bromo-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide,1-((6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methyl)-N-((7-ethynylimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide,N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-3-(difluoromethyl)-1H-pyrazole-4-carboxamide,ethyl3-(2-((4-(((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-pyrazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)acrylate,ethyl3-(2-((4-(((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-pyrazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)propanoate,3-(2-((4-(((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-pyrazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)propanoicacid,N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(morpholinomethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide,N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-3-(oxetan-3-yl)-1H-pyrazole-4-carboxamide,N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(2-methoxyethoxy)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide,1-((8-acetyl-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide,N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(2-hydroxypropan-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide,ethyl2-(2-((4-(((7-bromo-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-pyrazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)acetate,2-(2-((4-(((7-bromo-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-pyrazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)aceticacid,N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(3-hydroxypropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide,N-((7-bromo-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methyl)-1H-pyrazole-4-carboxamide,N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(2-hydroxy-2-methylpropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide,N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-2-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-2H-tetrazole-5-carboxamide,N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide,N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((8-cyano-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide,ethyl2-(4-(((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazol-3-yl)cyclopropane-1-carboxylate,N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(2-oxopyrrolidin-1-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide,ethyl1-(2-((4-(((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-pyrazol-1-yl)methyl)imidazo[1,2-a]pyridin-8-yl)cyclopropane-1-carboxylate,1-(2-((4-(((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-pyrazol-1-yl)methyl)imidazo[1,2-a]pyridin-8-yl)cyclopropane-1-carboxylicacid,N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((8-(1-(hydroxymethyl)cyclopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide,1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-((7-vinylimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide,N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(3-hydroxy-3-methylbutyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide,2-(4-(((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazol-3-yl)cyclopropane-1-carboxylicacid,N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-2-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-2H-1,2,3-triazole-4-carboxamide,N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(3-hydroxyoxetan-3-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide,N′-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-N-cyano-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboximidamide,N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-(1-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)ethyl)-1H-1,2,3-triazole-4-carboxamide,N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(2-methoxyethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide,3-((2H-tetrazol-5-yl)methyl)-N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide,ethyl2-(2-((4-(((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-pyrazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)cyclopropane-1-carboxylate,N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-5-((8-cyano-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1,3,4-oxadiazole-2-carboxamide,andN-((7-chloroimidazo[1,2-a]pyridin-2-yl)methyl)-1-((5,6-dimethylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide,N-((7-bromo-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((8-cyano-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide,N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(oxetan-3-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide,2-(2-((4-(((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-pyrazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)cyclopropane-1-carboxylicacid,N-((7-bromo-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide,N-((7-bromo-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-2-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-2H-tetrazole-5-carboxamide,N-((7-bromo-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-5-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1,3,4-oxadiazole-2-carboxamide,N-((7-bromo-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-5-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1,3,4-oxadiazole-2-carboxamide,N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-5-((6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methyl)-1,3,4-oxadiazole-2-carboxamide,N-((7-bromo-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide,N-((7-bromo-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-5-((6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methyl)-1,3,4-oxadiazole-2-carboxamide,N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(hydroxy(oxetan-3-yl)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide,N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-5-methoxyimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide,N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide,N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-5-fluoroimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide,N-((7-bromo-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-5-fluoroimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide,N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methyl)-1H-pyrazole-4-carboxamide,N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide,N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide,N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((8-cyano-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide,N-((7-bromo-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide,N-((7-bromo-6-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide,N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,4-triazole-3-carboxamide,N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(3-hydroxyoxetan-3-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide,N-((7-bromo-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-5-((8-cyano-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1,3,4-oxadiazole-2-carboxamide,1-((8-((1,3,4-oxadiazol-2-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide,N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-5-((6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methyl)-1,3,4-oxadiazole-2-carboxamide,ethyl2-(2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)acetate,2-(2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)aceticacid,N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-5-((8-cyano-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1,3,4-oxadiazole-2-carboxamide,N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(methylsulfonyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide,N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-5-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1-methyl-1H-1,2,4-triazole-3-carboxamide,N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-5-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-4H-1,2,4-triazole-3-carboxamide,ethyl3-(2-((4-(((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-pyrazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)-2,2-dimethylpropanoate,ethyl3-(2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)propanoate,3-(2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)propanoicacid,N-((7-bromo-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-5-fluoroimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide,N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyrimidin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide,ethyl2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-carboxylate,2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-carboxylicacid,N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(3-fluorooxetan-3-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide,ethyl3-(2-((4-(((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)-2,2-dimethylpropanoate,N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(oxetan-3-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide,3-(2-((4-(((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)-2,2-dimethylpropanoicacid,N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-fluoroimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide,1-((6-chloro-5-methylimidazo[1,2-a]pyridin-2-yl)methyl)-N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-1,2,3-triazole-4-carboxamide,N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-morpholinoimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide,N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(2H-tetrazol-5-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide,N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((5-cyclopropylpyrazolo[1,5-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide,N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-5-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)isoxazole-3-carboxamide,N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-5-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1,2,4-oxadiazole-3-carboxamide,N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((7-cyclopropyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide,N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(1H-tetrazol-1-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide,N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(4H-1,2,4-triazol-4-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide,N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(hydroxymethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide,N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-formylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide,1-((8-(3-amino-3-oxopropyl)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-1,2,3-triazole-4-carboxamide,N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((8-(2-cyanoethyl)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide,N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide,N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(oxetan-3-ylmethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide,1-((6-chloro-8-(oxetan-3-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-1,2,3-triazole-4-carboxamide,N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6,7-dichloroimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide,N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((5-cyclopropylthieno[2,3-b]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide,N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-3-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1,2,4-oxadiazole-5-carboxamide,N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((5-cyclopropylbenzofuran-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide,N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(difluoromethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide,1-((2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)methyl)-1H-pyrazole-4-carboxylicacid,1-((8-(2-(1H-tetrazol-5-yl)ethyl)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-1,2,3-triazole-4-carboxamide,N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-2-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)oxazole-4-carboxamide,N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-chlorobenzofuran-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide,N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-(1-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)ethyl)-1H-1,2,3-triazole-4-carboxamide,N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(2-oxotetrahydrofuran-3-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide,N-((7-bromo-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-fluoroimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide,1-((8-((1H-pyrazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-1,2,3-triazole-4-carboxamide,1-((2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)methyl)-1H-pyrazole-3-carboxylicacid,N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(2-oxopyrrolidin-1-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide,1-((8-bromo-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-1,2,3-triazole-4-carboxamide,ethyl3-(2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)-2,2-dimethylpropanoate,3-(2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)-2,2-dimethylpropanoicacid, ethyl2-((2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)oxy)acetate,2-((2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)oxy)aceticacid,N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylpyrazolo[1,5-a]pyrimidin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide,ethyl5-((2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)methyl)-1,3,4-oxadiazole-2-carboxylate,1-((8-((1,3,4-oxadiazol-2-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-1,2,3-triazole-4-carboxamide,N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((5-cyclopropyl-3-(trifluoromethyl)-1H-indol-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide,2-((2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)oxy)-2-methylpropanoicacid,N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(1-fluoroethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide,1-((8-((1,3,4-oxadiazol-2-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide,N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(oxetan-3-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide,N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(2-oxooxazolidin-3-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide,N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((7-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide,N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((5-cyclopropylbenzo[b]thiophen-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide,N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylbenzofuran-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide,N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(1H-pyrazol-1-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide,methyl1-((2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)methyl)cyclopentane-1-carboxylate,1-((2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)methyl)cyclopentane-1-carboxylicacid,1-((2-((4-(((7-chloro-8-ethoxyimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)methyl)cyclopentane-1-carboxylicacid,1-((6-chloro-1H-indol-2-yl)methyl)-N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-1,2,3-triazole-4-carboxamide,ethyl2-((2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)oxy)-2-methylpropanoate,methyl3-(2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)-2-fluoropropanoate,3-(2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)-2-fluoropropanoicacid,N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(isoxazol-4-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide,1-(2-((4-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methylcarbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)-1H-imidazole-4-carboxylicacid, ethyl3-(4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)-3-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)propanoate,3-(4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)-3-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)propanoicacid,3-(4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)-3-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)propanoicacid,N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylbenzo[b]thiophen-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide,1-(2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)-1H-pyrazole-4-carboxylicacid,N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1,5-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide,N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((5-cyclopropyl-1H-indol-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide,N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((5-cyclopropyl-1-methyl-1H-indol-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide,N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-chlorobenzo[b]thiophen-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide,N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-1H-indol-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide,N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((5-cyclopropyl-1H-benzo[d]imidazol-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide,N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((8-(2-cyano-2-methylpropyl)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide,N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(2-methyl-2-(2H-tetrazol-5-yl)propyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide,N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-7-fluoroimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide,N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-3-fluoroimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide,ethyl3-(2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)-3-hydroxy-2,2-dimethylpropanoate,3-(2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)-3-hydroxy-2,2-dimethylpropanoicacid,N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(1-ethyl-5,6-dioxo-5,6-dihydro-1,2,4-triazin-4(1H)-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide,N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-5-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)difluoromethyl)-1,3,4-oxadiazole-2-carboxamide,2-(2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-5-cyclopropyl-1H-indol-1-yl)aceticacid, ethyl3-(2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)-2-methylpropanoate,3-(2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)-2-methylpropanoicacid, methyl2-(2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-5-cyclopropyl-1H-indol-1-yl)acetate,N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(5,6-dioxo-5,6-dihydro-1,2,4-triazin-4(1H)-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide,ethyl4-(2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)-4H-1,2,4-triazole-3-carboxylate,N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(3-methyl-4H-1,2,4-triazol-4-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide,N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(2-oxa-6-azaspiro[3.3]heptan-6-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide,ethyl3-(2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-5-cyclopropyl-1H-indol-1-yl)propanoate,3-(2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-5-cyclopropyl-1H-indol-1-yl)propanoicacid,N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylbenzo[d]thiazol-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide,N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(3,5-dimethyl-4H-1,2,4-triazol-4-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide,methyl4-(2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-5-cyclopropyl-1H-indol-1-yl)benzoate,1-((5-chloro-7-cyclopropyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)methyl)-N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-1,2,3-triazole-4-carboxamide,N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylindolizin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide,N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(2-methylthiazol-5-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide,N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(3-methyl-1H-1,2,4-triazol-1-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide,4-(2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-5-cyclopropyl-1H-indol-1-yl)benzoicacid, ethyl4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-imidazole-2-carboxylate,4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-imidazole-2-carboxylicacid,N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((5-cyclopropyl-7-(2-oxopyrrolidin-1-yl)pyrazolo[1,5-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide,N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(thiazol-5-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide,4-(2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)morpholine-2-carboxylicacid, methyl1-(2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-b]pyridazin-8-yl)azetidine-3-carboxylate,1-(2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-b]pyridazin-8-yl)azetidine-3-carboxylicacid, methyl1-(2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-b]pyridazin-8-yl)pyrrolidine-3-carboxylate,1-(2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-b]pyridazin-8-yl)pyrrolidine-3-carboxylicacid, ethyl2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylindolizine-3-carboxylate,N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((1,2,3-trimethyl-1H-indol-5-yl)methyl)-1H-1,2,3-triazole-4-carboxamide,methyl4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrrole-2-carboxylate,4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrrole-2-carboxylicacid,N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-imidazole-4-carboxamide,methyl2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropyl-1H-indole-3-carboxylate,N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(hydroxy(3-(hydroxymethyl)oxetan-3-yl)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide,N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((8-cyano-3-cyclopropylquinolin-6-yl)methyl)-1H-1,2,3-triazole-4-carboxamide,2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropyl-1H-indole-3-carboxylicacid,6-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-3-cyclopropylquinoline-8-carboxamide,N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrrole-3-carboxamide,N-((7-chloro-6-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide,N-(1-(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)ethyl)-1-(1-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)ethyl)-1H-1,2,3-triazole-4-carboxamide,N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(hydroxy(oxetan-3-yl)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide,N-(1-(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)ethyl)-1-((6-cyclopropyl-8-(hydroxy(oxetan-3-yl)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide,N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-((N-(2,2,2-trifluoroethyl)sulfamoyl)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide,1-([1,2,4]triazolo[1,5-a]pyridin-2-ylmethyl)-N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide,N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-2-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-2H-tetrazole-5-carboxamide,N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-(imidazo[1,2-a]pyridin-2-ylmethyl)-1H-pyrazole-4-carboxamide,N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-(imidazo[1,2-b]pyridazin-2-ylmethyl)-1H-pyrazole-4-carboxamide,N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-(imidazo[1,2-a]pyridin-2-ylmethyl)-1H-1,2,3-triazole-4-carboxamide,1-([1,2,4]triazolo[1,5-a]pyridin-2-ylmethyl)-N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-1,2,3-triazole-4-carboxamide,N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methyl)-1H-imidazole-4-carboxamide,N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-2-((6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methyl)-2H-tetrazole-5-carboxamide,N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-(imidazo[1,2-b]pyridazin-2-ylmethyl)-1H-1,2,3-triazole-4-carboxamide,N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-(imidazo[1,2-b]pyridazin-2-ylmethyl)-1H-imidazole-4-carboxamide,N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-(quinoxalin-6-ylmethyl)-1H-1,2,3-triazole-4-carboxamide,N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-(quinoxalin-6-ylmethyl)-1H-pyrazole-4-carboxamide,1-((8-(4H-1,2,4-triazol-4-yl)imidazo[1,2-b]pyridazin-2-yl)methyl)-N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-1,2,3-triazole-4-carboxamide,N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(pyrrolidin-1-ylmethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide,N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((8-(oxetan-3-ylmethyl)imidazo[1,2-b]pyridazin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide,N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-(imidazo[1,2-a]pyridin-2-ylmethyl)-1H-imidazole-4-carboxamide,1-((8-(aminomethyl)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-1,2,3-triazole-4-carboxamide,N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-((2-(dimethylamino)ethoxy)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide,N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(((3,3,3-trifluoro-2-hydroxypropyl)amino)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide,N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-((2-hydroxyethoxy)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide,1-((8-((2-aminoethoxy)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-1,2,3-triazole-4-carboxamide,N-((7-bromoimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide,or a pharmaceutically acceptable salt thereof.

C. Pharmaceutical Compositions

In another aspect, the present invention provides pharmaceuticalcompositions comprising a compound of Formulae (I)-(V) or a compound ofFormulae (I)-(V) in combination with a pharmaceutically acceptableexcipient (e.g., carrier).

The pharmaceutical compositions include optical isomers, diastereomers,or pharmaceutically acceptable salts of the inhibitors disclosed herein.A compound of Formulae (I)-(III-d) included in the pharmaceuticalcomposition may be covalently attached to a carrier moiety, as describedabove. Alternatively, a compound of Formulae (I)-(V) included in thepharmaceutical composition is not covalently linked to a carrier moiety.

A “pharmaceutically acceptable carrier,” as used herein refers topharmaceutical excipients, for example, pharmaceutically,physiologically, acceptable organic or inorganic carrier substancessuitable for enteral or parenteral application that do not deleteriouslyreact with the active agent. Suitable pharmaceutically acceptablecarriers include water, salt solutions (such as Ringer's solution),alcohols, oils, gelatins, and carbohydrates such as lactose, amylose orstarch, fatty acid esters, hydroxymethycellulose, and polyvinylpyrrolidine. Such preparations can be sterilized and, if desired, mixedwith auxiliary agents such as lubricants, preservatives, stabilizers,wetting agents, emulsifiers, salts for influencing osmotic pressure,buffers, coloring, and/or aromatic substances and the like that do notdeleteriously react with the compounds of the invention.

The compounds of the invention can be administered alone or can becoadministered to the subject. Coadministration is meant to includesimultaneous or sequential administration of the compounds individuallyor in combination (more than one compound). The preparations can also becombined, when desired, with other active substances (e.g. to reducemetabolic degradation).

In some embodiments, a test agent as described herein can beincorporated into a pharmaceutical composition for administration bymethods known to those skilled in the art and described herein forprovided compounds.

D. Formulations

Compounds of the present invention can be prepared and administered in awide variety of oral, parenteral, and topical dosage forms. Thus, thecompounds of the present invention can be administered by injection(e.g. intravenously, intramuscularly, intracutaneously, subcutaneously,intraduodenally, or intraperitoneally). Also, the compounds describedherein can be administered by inhalation, for example, intranasally.Additionally, the compounds of the present invention can be administeredtransdermally. It is also envisioned that multiple routes ofadministration (e.g., intramuscular, oral, transdermal) can be used toadminister the compounds of the invention. Accordingly, the presentinvention also provides pharmaceutical compositions comprising apharmaceutically acceptable carrier or excipient and one or morecompounds of the invention.

For preparing pharmaceutical compositions from the compounds of thepresent invention, pharmaceutically acceptable carriers can be eithersolid or liquid. Solid form preparations include powders, tablets,pills, capsules, cachets, suppositories, and dispersible granules. Asolid carrier can be one or more substance that may also act asdiluents, flavoring agents, binders, preservatives, tabletdisintegrating agents, or an encapsulating material.

In powders, the carrier is a finely divided solid in a mixture with thefinely divided active component. In tablets, the active component ismixed with the carrier having the necessary binding properties insuitable proportions and compacted in the shape and size desired.

The powders and tablets preferably contain from 5% to 70% of the activecompound. Suitable carriers are magnesium carbonate, magnesium stearate,talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth,methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoabutter, and the like. The term “preparation” is intended to include theformulation of the active compound with encapsulating material as acarrier providing a capsule in which the active component with orwithout other carriers, is surrounded by a carrier, which is thus inassociation with it. Similarly, cachets and lozenges are included.Tablets, powders, capsules, pills, cachets, and lozenges can be used assolid dosage forms suitable for oral administration.

For preparing suppositories, a low melting wax, such as a mixture offatty acid glycerides or cocoa butter, is first melted and the activecomponent is dispersed homogeneously therein, as by stirring. The moltenhomogeneous mixture is then poured into convenient sized molds, allowedto cool, and thereby to solidify.

Liquid form preparations include solutions, suspensions, and emulsions,for example, water or water/propylene glycol solutions. For parenteralinjection, liquid preparations can be formulated in solution in aqueouspolyethylene glycol solution.

When parenteral application is needed or desired, particularly suitableadmixtures for the compounds of the invention are injectable, sterilesolutions, preferably oily or aqueous solutions, as well as suspensions,emulsions, or implants, including suppositories. In particular, carriersfor parenteral administration include aqueous solutions of dextrose,saline, pure water, ethanol, glycerol, propylene glycol, peanut oil,sesame oil, polyoxyethylene-block polymers, and the like. Ampoules areconvenient unit dosages. The compounds of the invention can also beincorporated into liposomes or administered via transdermal pumps orpatches. Pharmaceutical admixtures suitable for use in the presentinvention include those described, for example, in PharmaceuticalSciences (17th Ed., Mack Pub. Co., Easton, Pa.) and WO 96/05309, theteachings of both of which are hereby incorporated by reference.

Aqueous solutions suitable for oral use can be prepared by dissolvingthe active component in water and adding suitable colorants, flavors,stabilizers, and thickening agents as desired. Aqueous suspensionssuitable for oral use can be made by dispersing the finely dividedactive component in water with viscous material, such as natural orsynthetic gums, resins, methylcellulose, sodium carboxymethylcellulose,and other well-known suspending agents.

Also included are solid form preparations that are intended to beconverted, shortly before use, to liquid form preparations for oraladministration. Such liquid forms include solutions, suspensions, andemulsions. These preparations may contain, in addition to the activecomponent, colorants, flavors, stabilizers, buffers, artificial andnatural sweeteners, dispersants, thickeners, solubilizing agents, andthe like.

The pharmaceutical preparation is preferably in unit dosage form. Insuch form the preparation is subdivided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofpreparation, such as packeted tablets, capsules, and powders in vials orampoules. Also, the unit dosage form can be a capsule, tablet, cachet,or lozenge itself, or it can be the appropriate number of any of thesein packaged form.

The quantity of active component in a unit dose preparation may bevaried or adjusted from 0.1 mg to 10000 mg, more typically 1.0 mg to1000 mg, most typically 10 mg to 500 mg, according to the particularapplication and the potency of the active component. The compositioncan, if desired, also contain other compatible therapeutic agents.

Some compounds may have limited solubility in water and therefore mayrequire a surfactant or other appropriate co-solvent in the composition.Such co-solvents include: Polysorbate 20, 60, and 80; Pluronic F-68,F-84, and P-103; cyclodextrin; and polyoxyl 35 castor oil. Suchco-solvents are typically employed at a level between about 0.01% andabout 2% by weight.

Viscosity greater than that of simple aqueous solutions may be desirableto decrease variability in dispensing the formulations, to decreasephysical separation of components of a suspension or emulsion offormulation, and/or otherwise to improve the formulation. Such viscositybuilding agents include, for example, polyvinyl alcohol, polyvinylpyrrolidone, methyl cellulose, hydroxy propyl methylcellulose,hydroxyethyl cellulose, carboxymethyl cellulose, hydroxy propylcellulose, chondroitin sulfate and salts thereof, hyaluronic acid andsalts thereof, and combinations of the foregoing. Such agents aretypically employed at a level between about 0.01% and about 2% byweight.

The compositions of the present invention may additionally includecomponents to provide sustained release and/or comfort. Such componentsinclude high molecular weight, anionic mucomimetic polymers, gellingpolysaccharides, and finely-divided drug carrier substrates. Thesecomponents are discussed in greater detail in U.S. Pat. Nos. 4,911,920;5,403,841; 5,212,162; and 4,861,760. The entire contents of thesepatents are incorporated herein by reference in their entirety for allpurposes.

E. Effective Dosages

Pharmaceutical compositions provided by the present invention includecompositions wherein the active ingredient is contained in atherapeutically effective amount, i.e., in an amount effective toachieve its intended purpose. The actual amount effective for aparticular application will depend, inter alia, on the condition beingtreated. For example, when administered in methods to treat HAE, suchcompositions will contain an amount of active ingredient effective toachieve the desired result (e.g. inhibiting pKal and/or decreasing theamount of bradykinin in a subject).

The dosage and frequency (single or multiple doses) of compoundadministered can vary depending upon a variety of factors, includingroute of administration; size, age, sex, health, body weight, body massindex, and diet of the recipient; nature and extent of symptoms of thedisease being treated (e.g., the disease responsive to pKal inhibition);presence of other diseases or other health-related problems; kind ofconcurrent treatment; and complications from any disease or treatmentregimen. Other therapeutic regimens or agents can be used in conjunctionwith the methods and compounds of the invention.

For any provided compound or test agent, the therapeutically effectiveamount can be initially determined from cell culture assays. Targetconcentrations will be those concentrations of active compound(s) thatare capable of decreasing pKal enzymatic activity as measured, forexample, using the methods described.

Therapeutically effective amounts for use in humans may be determinedfrom animal models. For example, a dose for humans can be formulated toachieve a concentration that has been found to be effective in animals.The dosage in humans can be adjusted by monitoring pKal inhibition andadjusting the dosage upwards or downwards, as described above.

Dosages may be varied depending upon the requirements of the patient andthe compound being employed. The dose administered to a patient, in thecontext of the present invention, should be sufficient to effect abeneficial therapeutic response in the patient over time. The size ofthe dose also will be determined by the existence, nature, and extent ofany adverse side effects. Generally, treatment is initiated with smallerdosages, which are less than the optimum dose of the compound.Thereafter, the dosage is increased by small increments until theoptimum effect under circumstances is reached. In some embodiments, thedosage range is 0.001% to 10% (w/v). In some embodiments, the dosagerange is 0.1% to 5% (w/v).

Dosage amounts and intervals can be adjusted individually to providelevels of the administered compound effective for the particularclinical indication being treated. This will provide a therapeuticregimen that is commensurate with the severity of the individual'sdisease state.

F. Methods of Treatment

The present disclosure provides compounds for use in medicine. Thepresent disclosure further provides the use of any compounds describedherein for inhibiting the activity of pKal, which would be beneficial totreatment of pKal-mediated diseases and conditions. ExemplarypKal-mediated disorders include edema, which refers to swelling in thewhole body of a subject or a part thereof due to inflammation or injurywhen small blood vessels become leaky and releases fluid into nearbytissues. In some examples, the edema is HAE. In other examples, theedema occurs in eyes, e.g., diabetic macular edema (DME). The presentdisclosure provides methods of inhibiting the activity of pKal. Incertain embodiments, the application provides a method of inhibiting theactivity of pKal in vitro via contacting any of the compounds describedherein with pKal molecules in a sample, such as a biological sample. Incertain embodiments, the application provides a method of inhibiting theactivity of pKal in vivo via delivering an effective amount of any ofthe compounds described herein to a subject in need of the treatmentthrough a suitable route.

In certain embodiments, the methods comprise administering to a subjectin need thereof (e.g., a subject such as a human patient with edema) anyof the compounds described herein or a pharmaceutically acceptable saltthereof. In certain embodiments, the methods comprise administering acompound of Formulae (I)-(V), or a pharmaceutically acceptable salt orcomposition thereof, to a subject in need thereof. In some embodiments,the method comprises administering a pharmaceutical compositioncomprising a compound of Formulae (I)-(V), or a pharmaceuticallyacceptable salt to a subject in need thereof.

In certain embodiments, the subject to be treated by any of the methodsdescribed herein is a human patient having, suspected of having, or atrisk for edema, for example, HAE or diabetic macular edema (DME). Asubject having an edema can be identified by routine medicalexamination, e.g., laboratory tests. A subject suspected of having anedema might show one or more symptoms of the disease/disorder. A subjectat risk for edema can be a subject having one or more of the riskfactors associated with the disease, for example, deficiency in C1-INHas for HAE.

In certain embodiments, provided herein are methods of alleviating oneor more symptoms of HAE in a human patient who is suffering from an HAEattack. Such a patient can be identified by routine medical procedures.An effective amount of one or more of the provided compounds can begiven to the human patient via a suitable route, for example, thosedescribed herein. The compounds described herein may be used alone, ormay be used in combination with other anti-HAE agents, for example, a C1esterase inhibitor (e.g., Cinryze® or Berinert®), a pKal inhibitor(e.g., ecallantide or lanadelumab) or a bradykinin B2 receptorantagonist (e.g., Firazyr®).

In other embodiments, provided herein are methods or reducing the riskof HAE attack in a human HAE patient who is in quiescent stage. Such apatient can be identified based on various factors, including history ofHAE attack. An effective amount of one or more of the compounds can begiven to the human patient via a suitable route, for example, thosedescribed herein. The compounds described herein may be used alone, ormay be used in combination with other anti-HAE agents, for example, a C1esterase inhibitor (e.g., Cinryze® or Berinert®), a pKal inhibitor(e.g., ecallantide or lanadelumab) or a bradykinin B2 receptorantagonist (e.g., Firazyr®).

In yet other embodiments, provided herein are prophylactic treatment ofHAE in human patients having risk to HAE attacks with one or more of thecompounds described herein. Patients suitable for such prophylactictreatment may be human subjects having history of HAE attacks (e.g.,human subjects experiencing more than 2 attacks per month).Alternatively, patients suitable for the prophylactic treatment may behuman subjects having no HAE attack history but bearing one or more riskfactors for HAE (e.g., family history, genetic defects in C1-INH gene,etc.) Such prophylactic treatment may involve the compounds describedherein as the sole active agent, or involve additional anti-HAE agents,such as those described herein.

In certain embodiments, provided herein are methods for preventing orreducing edema in an eye of a subject (e.g., a human patient). In someexamples, the human patient is a diabetic having, suspected of having,or at risk for diabetic macular edema (DME). DME is the proliferativeform of diabetic retinopathy characterized by swelling of the retinallayers, neovascularization, vascular leak, and retinal thickening indiabetes mellitus due to leaking of fluid from blood vessels within themacula. To practice this method, an effective amount of one or more ofthe compounds described herein, or pharmaceutically acceptable saltsthereof, may be delivered into the eye of the subject where treatment isneeded. For example, the compound may be delivered by intraocularinjection, or intravitreal injection. A subject may be treated with thecompound as described herein, either as the sole active agent, or incombination with another treatment for DME. Non-limiting examples oftreatment for DME include laser photocoagulation, steroids, VEGF pathwaytargeting agents (e.g., Lucentis® (ranibizumab) or Eylea®(aflibercept)), and/or anti-PDGF agents.

In certain embodiments, the methods disclosed herein compriseadministering to the subject an effective amount of a compound ofFormulae (I)-(V), or a pharmaceutically acceptable salt or compositionthereof. In some embodiments, the effective amount is a therapeuticallyeffective amount. In some embodiments, the effective amount is aprophylactically effective amount.

In certain embodiments, the subject being treated is an animal. Theanimal may be of either sex and may be at any stage of development. Incertain embodiments, the subject is a mammal. In certain embodiments,the subject being treated is a human. In certain embodiments, thesubject is a domesticated animal, such as a dog, cat, cow, pig, horse,sheep, or goat. In certain embodiments, the subject is a companionanimal, such as a dog or cat. In certain embodiments, the subject is alivestock animal, such as a cow, pig, horse, sheep, or goat. In certainembodiments, the subject is a zoo animal. In another embodiment, thesubject is a research animal such as a rodent (e.g., mouse, rat), dog,pig, or non-human primate. In certain embodiments, the animal is agenetically engineered animal. In certain embodiments, the animal is atransgenic animal.

Certain methods described herein may comprise administering one or moreadditional pharmaceutical agent(s) in combination with the compoundsdescribed herein. The additional pharmaceutical agent(s) may beadministered at the same time as the compound of Formulae (I)-(V), or atdifferent times than the compound of Formulae (I)-(V). For example, thecompound of Formulae (I)-(V) and any additional pharmaceutical agent(s)may be on the same dosing schedule or different dosing schedules. All orsome doses of the compound of Formulae (I)-(V) may be administeredbefore all or some doses of an additional pharmaceutical agent, afterall or some does an additional pharmaceutical agent, within a dosingschedule of an additional pharmaceutical agent, or a combinationthereof. The timing of administration of the compound of Formulae(I)-(V) and additional pharmaceutical agents may be different fordifferent additional pharmaceutical agents.

In certain embodiments, the additional pharmaceutical agent comprises anagent useful in the treatment of an edema, such as HAE or DME. Examplesof such agents are provided herein.

The following numbered embodiments, while non-limiting, are exemplary ofcertain aspects of the present disclosure:

1. A compound of Formula (I):

or a pharmaceutically acceptable salt thereof,wherein:

-   Cy^(A) is selected from 3- to 7-membered saturated or partially    unsaturated monocyclic heterocyclyenel having 1-2 heteroatoms    selected from oxygen, nitrogen, or sulfur, 5- to 6-membered    heteroarylene having 1-4 heteroatoms selected from oxygen, nitrogen,    or sulfur, 7- to 10-membered saturated or partially unsaturated    bicyclic heterocyclylene having 1-4 heteroatoms selected from    oxygen, nitrogen, or sulfur, and 7- to 10-membered bicyclic    heteroarylene having 1-4 heteroatoms selected from oxygen, nitrogen,    or sulfur, wherein Cy^(A) is substituted with 0-4 R^(A) groups;-   each R^(A) is independently selected from halogen, —CN, —C(R)═N(R),    —C(O)R, —C(O)₂R, —C(O)N(R)₂, —NO₂, —N(R)—N(R)₂, —N(R)₂, —N(R)C(O)R,    —N(R)C(O)₂R, —N(R)C(O)N(R)₂, —N(R)S(O)₂R, —OR, —OC(O)R, —OC(O)N(R)₂,    —SR, —S(O)R, —S(O)₂R, —S(O)N(R)₂, —S(O)₂N(R)₂, or an optionally    substituted group selected from C₁₋₆ aliphatic, phenyl, 5- to    6-membered heteroaryl having 1-4 heteroatoms selected from oxygen,    nitrogen, or sulfur, 3- to 7-membered saturated or partially    unsaturated monocyclic carbocyclyl, and 3- to 7-membered saturated    or partially unsaturated monocyclic heterocyclyl having 1-2    heteroatoms selected from oxygen, nitrogen, or sulfur;-   Cy^(B) is selected from 3- to 7-membered saturated or partially    unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected    from oxygen, nitrogen, or sulfur, 5- to 6-membered heteroaryl having    1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 7- to    10-membered saturated or partially unsaturated bicyclic heterocyclyl    having 1-5 heteroatoms selected from oxygen, nitrogen, or sulfur,    and 7- to 10-membered bicyclic heteroaryl having 1-5 heteroatoms    selected from oxygen, nitrogen, or sulfur, wherein Cy^(B) is    substituted with 0-5 R^(B) groups;-   each R^(B) is independently selected from halogen, —CN, —C(R)═N(R),    —C(O)R, —C(O)₂R, —C(O)N(R)₂, —NO₂, —N(R)—N(R)₂, —N(R)₂, —N(R)C(O)R,    —N(R)C(O)₂R, —N(R)C(O)N(R)₂, —N(R)S(O)₂R, —OR, —OC(O)R, —OC(O)N(R)₂,    —SR, —S(O)R, —S(O)₂R, —S(O)N(R)₂, —S(O)₂N(R)₂, or an optionally    substituted group selected from C₁₋₆ aliphatic, phenyl, 5- to    6-membered heteroaryl having 1-4 heteroatoms selected from oxygen,    nitrogen, or sulfur, 3- to 7-membered saturated or partially    unsaturated monocyclic carbocyclyl, and 3- to 7-membered saturated    or partially unsaturated monocyclic heterocyclyl having 1-2    heteroatoms selected from oxygen, nitrogen, or sulfur;-   L is selected from -QC(R)₂—, —C(R)₂Q-, -QC(Q)-, —C(Q)Q-,    —C(R)₂QC(O)—, and —C(O)QC(R)₂—, wherein each Q is independently a    monovalent or divalent group as valency allows, selected from the    group consisting of O, N(R), or (S);-   R¹, R², R³, and R⁴ are independently selected from hydrogen and C₁₋₆    aliphatic;-   R⁵, R⁶, R⁷, R⁸, and R⁹ are independently selected from hydrogen,    halogen, —CN, —C(R)═N(R), —C(O)R, —C(O)₂R, —C(O)N(R)₂, —NO₂,    —N(R)—N(R)₂, —N(R)₂, —N(R)C(O)R, —N(R)C(O)₂R, —N(R)C(O)N(R)₂,    —N(R)S(O)₂R, —OR, —OC(O)R, —OC(O)N(R)₂, —SR, —S(O)R, —S(O)₂R,    —S(O)N(R)₂, —S(O)₂N(R)₂, or an optionally substituted group selected    from C₁₋₆ aliphatic, phenyl, 5- to 6-membered heteroaryl having 1-4    heteroatoms selected from oxygen, nitrogen, or sulfur, 3- to    7-membered saturated or partially unsaturated monocyclic    carbocyclyl, and 3- to 7-membered saturated or partially unsaturated    monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen,    nitrogen, or sulfur; and-   each R is independently hydrogen, —CN, or an optionally substituted    group selected from C₁₋₆ aliphatic, phenyl, 5- to 6-membered    heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or    sulfur, 3- to 7-membered saturated or partially unsaturated    monocyclic carbocyclyl, and 3- to 7-membered saturated or partially    unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected    from oxygen, nitrogen, or sulfur;-   or two R groups on the same carbon or nitrogen are taken together    with their intervening atoms to form a ring selected from 3- to    7-membered saturated or partially unsaturated monocyclic ring having    0-2 heteroatoms selected from oxygen, nitrogen, or sulfur, and 5- to    6-membered heteroaryl having 1-4 heteroatoms selected from oxygen,    nitrogen, or sulfur;-   with the proviso that the compound is other than    N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-2-((3-chloroquinolin-6-yl)methyl)isonicotinamide.    2. The compound of embodiment 1, wherein the compound is of Formula    (IV):

or a pharmaceutically acceptable salt thereof,wherein:

-   Cy^(A) is a 5-membered heteroarylene having 1-4 heteroatoms selected    from oxygen or nitrogen, wherein Cy^(A) is substituted with 0-3    R^(A) groups;-   L is selected from —NC(O)— and —C(O)N—;-   R⁶, R⁸, and R⁹ are independently selected from hydrogen, halogen,    —CN, —C(R)═N(R), —C(O)R, —C(O)₂R, —C(O)N(R)₂, —NO₂, —N(R)—N(R)₂,    —N(R)₂, —N(R)C(O)R, —N(R)C(O)₂R, —N(R)C(O)N(R)₂, —N(R)S(O)₂R, —OR,    —OC(O)R, —OC(O)N(R)₂, —SR, —S(O)R, —S(O)₂R, —S(O)N(R)₂, —S(O)₂N(R)₂,    or an optionally substituted group selected from C₁₋₆ aliphatic,    phenyl, 5- to 6-membered heteroaryl having 1-4 heteroatoms selected    from oxygen, nitrogen, or sulfur, 3- to 7-membered saturated or    partially unsaturated monocyclic carbocyclyl, and 3- to 7-membered    saturated or partially unsaturated monocyclic heterocyclyl having    1-2 heteroatoms selected from oxygen, nitrogen, or sulfur;-   R⁷ is —F, —Cl, or —Br;-   W⁴ is carbon or nitrogen;-   R¹⁰ and R¹¹ are each optionally present, and if present are    independently selected from halogen, —CN, —C(R)═N(R), —C(O)R,    —C(O)₂R, —C(O)N(R)₂, —NO₂, —N(R)—N(R)₂, —N(R)₂, —N(R)C(O)R,    —N(R)C(O)₂R, —N(R)C(O)N(R)₂, —N(R)S(O)₂R, —OR, —OC(O)R, —OC(O)N(R)₂,    —SR, —S(O)R, —S(O)₂R, —S(O)N(R)₂, —S(O)₂N(R)₂, or an optionally    substituted group selected from C₁₋₆ aliphatic, phenyl, 5- to    6-membered heteroaryl having 1-4 heteroatoms selected from oxygen,    nitrogen, or sulfur, 3- to 7-membered saturated or partially    unsaturated monocyclic carbocyclyl, and 3- to 7-membered saturated    or partially unsaturated monocyclic heterocyclyl having 1-2    heteroatoms selected from oxygen, nitrogen, or sulfur;-   R¹³ is selected from halogen, —CN, —C(R)═N(R), —C(O)R, —C(O)₂R,    —C(O)N(R)₂, —NO₂, —N(R)—N(R)₂, —N(R)₂, —N(R)C(O)R, —N(R)C(O)₂R,    —N(R)C(O)N(R)₂, —N(R)S(O)₂R, —OR, —OC(O)R, —OC(O)N(R)₂, —SR, —S(O)R,    —S(O)₂R, —S(O)N(R)₂, —S(O)₂N(R)₂, or an optionally substituted group    selected from C₂₋₆ aliphatic, phenyl, 5- to 6-membered heteroaryl    having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 3-    to 7-membered saturated or partially unsaturated monocyclic    carbocyclyl, and 3- to 7-membered saturated or partially unsaturated    monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen,    nitrogen, or sulfur;-   R¹⁴ is optionally present, and if present and is selected from    halogen, —CN, —C(R)═N(R), —C(O)R, —C(O)₂R, —C(O)N(R)₂, —NO₂,    —N(R)—N(R)₂, —N(R)C(O)R, —N(R)C(O)₂R, —N(R)C(O)N(R)₂, —N(R)S(O)₂R,    —OC(O)R, —OC(O)N(R)₂, —SR, —S(O)R, —S(O)₂R, —S(O)N(R)₂, —S(O)₂N(R)₂,    or an optionally substituted group selected from C₃₋₆ aliphatic,    phenyl, 5- to 6-membered heteroaryl having 1-4 heteroatoms selected    from oxygen, nitrogen, or sulfur, 3- to 7-membered saturated or    partially unsaturated monocyclic carbocyclyl, and 3- to 7-membered    saturated or partially unsaturated monocyclic heterocyclyl having    1-2 heteroatoms selected from oxygen, nitrogen, or sulfur; and-   each R is independently hydrogen, —CN, or an optionally substituted    group selected from C₁₋₆ aliphatic, phenyl, 5- to 6-membered    heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or    sulfur, 3- to 7-membered saturated or partially unsaturated    monocyclic carbocyclyl, and 3- to 7-membered saturated or partially    unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected    from oxygen, nitrogen, or sulfur;-   or two R groups on the same carbon or nitrogen are taken together    with their intervening atoms to form a ring selected from 3- to    7-membered saturated or partially unsaturated monocyclic ring having    0-2 heteroatoms selected from oxygen, nitrogen, or sulfur, and 5- to    6-membered heteroaryl having 1-4 heteroatoms selected from oxygen,    nitrogen, or sulfur.    3. The compound of any one of the preceding embodiments, wherein the    compound is of Formula (V):

or a pharmaceutically acceptable salt thereof,wherein:

-   Cy^(A) is a 5-membered heteroarylene having 1-4 nitrogens, wherein    when Cy^(A) comprises 3 nitrogens, Cy^(A) is not

-   L is selected from —NC(O)— and —C(O)N—;-   R⁶, R, and R⁹ are independently selected from hydrogen, halogen,    —CN, —C(R)═N(R), —C(O)R, —C(O)₂R, —C(O)N(R)₂, —NO₂, —N(R)—N(R)₂,    —N(R)₂, —N(R)C(O)R, —N(R)C(O)₂R, —N(R)C(O)N(R)₂, —N(R)S(O)₂R, —OR,    —OC(O)R, —OC(O)N(R)₂, —SR, —S(O)R, —S(O)₂R, —S(O)N(R)₂, —S(O)₂N(R)₂,    or an optionally substituted group selected from C₁₋₆ aliphatic,    phenyl, 5- to 6-membered heteroaryl having 1-4 heteroatoms selected    from oxygen, nitrogen, or sulfur, 3- to 7-membered saturated or    partially unsaturated monocyclic carbocyclyl, and 3- to 7-membered    saturated or partially unsaturated monocyclic heterocyclyl having    1-2 heteroatoms selected from oxygen, nitrogen, or sulfur;-   R⁷ is —F, —Cl, or —Br;-   R¹⁰ is optionally present, and if present is selected from halogen,    —CN, —C(R)═N(R), —C(O)R, —C(O)₂R, —C(O)N(R)₂, —NO₂, —N(R)—N(R)₂,    —N(R)₂, —N(R)C(O)R, —N(R)C(O)₂R, —N(R)C(O)N(R)₂, —N(R)S(O)₂R, —OR,    —OC(O)R, —OC(O)N(R)₂, —SR, —S(O)R, —S(O)₂R, —S(O)N(R)₂, —S(O)₂N(R)₂,    or an optionally substituted group selected from C₁₋₆ aliphatic,    phenyl, 5- to 6-membered heteroaryl having 1-4 heteroatoms selected    from oxygen, nitrogen, or sulfur, 3- to 7-membered saturated or    partially unsaturated monocyclic carbocyclyl, and 3- to 7-membered    saturated or partially unsaturated monocyclic heterocyclyl having    1-2 heteroatoms selected from oxygen, nitrogen, or sulfur;-   R¹¹ is optionally present, and if present is selected from halogen,    —CN, —C(R)═N(R), —C(O)R, —C(O)N(R)₂, —NO₂, —N(R)—N(R)₂, —N(R)₂,    —N(R)C(O)R, —N(R)C(O)₂R, —N(R)C(O)N(R)₂, —N(R)S(O)₂R, —OR, —OC(O)R,    —OC(O)N(R)₂, —SR, —S(O)R, —S(O)₂R, —S(O)N(R)₂, —S(O)₂N(R)₂, or an    optionally substituted group selected from C₁, aliphatic, phenyl, 5-    to 6-membered heteroaryl having 1-4 heteroatoms selected from    oxygen, nitrogen, or sulfur, 3- to 7-membered saturated or partially    unsaturated monocyclic carbocyclyl, and 3- to 7-membered saturated    or partially unsaturated monocyclic heterocyclyl having 1-2    heteroatoms selected from oxygen, nitrogen, or sulfur;-   R¹³ is selected from —CN, —C(R)═N(R), —C(O)R, —C(O)₂R, —C(O)N(R)₂,    —NO₂, —N(R)—N(R)₂, —N(R)₂, —N(R)C(O)R, —N(R)C(O)₂R, —N(R)C(O)N(R)₂,    —N(R)S(O)₂R, —OR, —OC(O)R, —OC(O)N(R)₂, —SR, —S(O)R, —S(O)₂R,    —S(O)N(R)₂, —S(O)₂N(R)₂, or an optionally substituted group selected    from phenyl, 5- to 6-membered heteroaryl having 1-4 heteroatoms    selected from oxygen, nitrogen, or sulfur, 3- or 5-7-membered    saturated or partially unsaturated monocyclic carbocyclyl, and 3- to    7-membered saturated or partially unsaturated monocyclic    heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen,    or sulfur;-   R¹⁴ is optionally present, and if present and is selected from    halogen, —CN, —C(R)═N(R), —C(O)R, —C(O)₂R, —C(O)N(R)₂, —NO₂,    —N(R)—N(R)₂, —N(R)C(O)R, —N(R)C(O)₂R, —N(R)C(O)N(R)₂, —N(R)S(O)₂R,    —OC(O)R, —OC(O)N(R)₂, —SR, —S(O)R, —S(O)₂R, —S(O)N(R)₂, —S(O)₂N(R)₂,    or an optionally substituted group selected from C₃₋₆ aliphatic,    phenyl, 5- to 6-membered heteroaryl having 1-4 heteroatoms selected    from oxygen, nitrogen, or sulfur, 3- to 7-membered saturated or    partially unsaturated monocyclic carbocyclyl, and 3- to 7-membered    saturated or partially unsaturated monocyclic heterocyclyl having    1-2 heteroatoms selected from oxygen, nitrogen, or sulfur; and-   each R is independently hydrogen, —CN, or an optionally substituted    group selected from C₁₋₆ aliphatic, phenyl, 5- to 6-membered    heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or    sulfur, 3- to 7-membered saturated or partially unsaturated    monocyclic carbocyclyl, and 3- to 7-membered saturated or partially    unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected    from oxygen, nitrogen, or sulfur;-   or two R groups on the same carbon or nitrogen are taken together    with their intervening atoms to form a ring selected from 3- to    7-membered saturated or partially unsaturated monocyclic ring having    0-2 heteroatoms selected from oxygen, nitrogen, or sulfur, and 5- to    6-membered heteroaryl having 1-4 heteroatoms selected from oxygen,    nitrogen, or sulfur.    4. The compound of any one of the preceding embodiments, wherein L    is selected from -QC(R)₂—, —C(R)₂Q-, —C(Q)Q-, or —C(R)₂QC(O)—,    wherein Q is independently a monovalent or divalent group as valency    allows, selected from O or N(R).    5. The compound of any one of of the preceding embodiments, wherein    L is —N(H)C(O)—.    6. The compound of any one of of the preceding embodiments, L is    —C(O)N(H)—. The compound of any one of the preceding embodiments,    wherein L is selected from the group consisting of:

wherein # represents to point of attachment to Cy^(A).7. The compound of any one of the preceding embodiments, wherein L isselected from the group consisting of:

wherein # represents to point of attachment to Cy^(A).8. The compound of any one of the preceding embodiments, wherein L is:

wherein # represents to point of attachment to Cy^(A).9. The compound of any one of the preceding embodiments, wherein R³ andR⁴ are hydrogen.10. The compound of any one of the preceding embodiments, wherein thecompound is of Formula (II):

or a pharmaceutically acceptable salt thereof,wherein:

-   Cy^(A) is selected from 3- to 7-membered saturated or partially    unsaturated monocyclic heterocyclyenel having 1-2 heteroatoms    selected from oxygen, nitrogen, or sulfur, 5- to 6-membered    heteroarylene having 1-4 heteroatoms selected from oxygen, nitrogen,    or sulfur, 7- to 10-membered saturated or partially unsaturated    bicyclic heterocyclylene having 1-4 heteroatoms selected from    oxygen, nitrogen, or sulfur, and 7- to 10-membered bicyclic    heteroarylene having 1-4 heteroatoms selected from oxygen, nitrogen,    or sulfur, wherein Cy^(A) is substituted with 0-4 R^(A) groups;-   each R^(A) is independently selected from halogen, —CN, —C(R)═N(R),    —C(O)R, —C(O)₂R, —C(O)N(R)₂, —NO₂, —N(R)—N(R)₂, —N(R)₂, —N(R)C(O)R,    —N(R)C(O)₂R, —N(R)C(O)N(R)₂, —N(R)S(O)₂R, —OR, —OC(O)R, —OC(O)N(R)₂,    —SR, —S(O)R, —S(O)₂R, —S(O)N(R)₂, —S(O)₂N(R)₂, or an optionally    substituted group selected from C₁₋₆ aliphatic, phenyl, 5- to    6-membered heteroaryl having 1-4 heteroatoms selected from oxygen,    nitrogen, or sulfur, 3- to 7-membered saturated or partially    unsaturated monocyclic carbocyclyl, and 3- to 7-membered saturated    or partially unsaturated monocyclic heterocyclyl having 1-2    heteroatoms selected from oxygen, nitrogen, or sulfur;-   Cy^(B) is selected from 3- to 7-membered saturated or partially    unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected    from oxygen, nitrogen, or sulfur, 5- to 6-membered heteroaryl having    1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 7- to    10-membered saturated or partially unsaturated bicyclic heterocyclyl    having 1-5 heteroatoms selected from oxygen, nitrogen, or sulfur,    and 7- to 10-membered bicyclic heteroaryl having 1-5 heteroatoms    selected from oxygen, nitrogen, or sulfur, wherein Cy^(B) is    substituted with 0-5 R^(B) groups;-   each R^(B) is independently selected from halogen, —CN, —C(R)═N(R),    —C(O)R, —C(O)₂R, —C(O)N(R)₂, —NO₂, —N(R)—N(R)₂, —N(R)₂, —N(R)C(O)R,    —N(R)C(O)₂R, —N(R)C(O)N(R)₂, —N(R)S(O)₂R, —OR, —OC(O)R, —OC(O)N(R)₂,    —SR, —S(O)R, —S(O)₂R, —S(O)N(R)₂, —S(O)₂N(R)₂, or an optionally    substituted group selected from C₁₋₆ aliphatic, phenyl, 5- to    6-membered heteroaryl having 1-4 heteroatoms selected from oxygen,    nitrogen, or sulfur, 3- to 7-membered saturated or partially    unsaturated monocyclic carbocyclyl, and 3- to 7-membered saturated    or partially unsaturated monocyclic heterocyclyl having 1-2    heteroatoms selected from oxygen, nitrogen, or sulfur;-   R¹ and R² are independently selected from hydrogen and C₁₋₆    aliphatic;-   R⁶ and R⁷ are independently selected from hydrogen, halogen, —CN,    —C(R)═N(R), —C(O)R, —C(O)₂R, —C(O)N(R)₂, —NO₂, —N(R)—N(R)₂, —N(R)₂,    —N(R)C(O)R, —N(R)C(O)₂R, —N(R)C(O)N(R)₂, —N(R)S(O)₂R, —OR, —OC(O)R,    —OC(O)N(R)₂, —SR, —S(O)R, —S(O)₂R, —S(O)N(R)₂, —S(O)₂N(R)₂, or an    optionally substituted group selected from C₁₋₆ aliphatic, phenyl,    5- to 6-membered heteroaryl having 1-4 heteroatoms selected from    oxygen, nitrogen, or sulfur, 3- to 7-membered saturated or partially    unsaturated monocyclic carbocyclyl, and 3- to 7-membered saturated    or partially unsaturated monocyclic heterocyclyl having 1-2    heteroatoms selected from oxygen, nitrogen, or sulfur; and-   each R is independently hydrogen, —CN, or an optionally substituted    group selected from C₁₋₆ aliphatic, phenyl, 5- to 6-membered    heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or    sulfur, 3- to 7-membered saturated or partially unsaturated    monocyclic carbocyclyl, and 3- to 7-membered saturated or partially    unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected    from oxygen, nitrogen, or sulfur;-   or two R groups on the same carbon or nitrogen are taken together    with their intervening atoms to form a ring selected from 3- to    7-membered saturated or partially unsaturated monocyclic ring having    0-2 heteroatoms selected from oxygen, nitrogen, or sulfur, and 5- to    6-membered heteroaryl having 1-4 heteroatoms selected from oxygen,    nitrogen, or sulfur;-   with the proviso that the compound is other than    N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-2-((3-chloroquinolin-6-yl)methyl)isonicotinamide.    11. The compound of any one of the preceding embodiments, with the    proviso that Cy^(A) is a group other than pyridinediyl and the    compound is other than    N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-2-((3-chloroquinolin-6-yl)methyl)isonicotinamide.    12. The compound of any one of the preceding embodiments, wherein    Cy^(A) is selected from 5- to 6-membered heteroaryl having 1-4    heteroatoms selected from oxygen, nitrogen, or sulfur, and 7- to    10-membered bicyclic heteroaryl having 1-4 heteroatoms selected from    oxygen, nitrogen, or sulfur wherein Cy^(A) is substituted with 0-4    R^(A) groups.    13. The compound of any one of the preceding embodiments, wherein    Cy^(A) is a 6-membered heteroarylene having 1-4 heteroatoms selected    from oxygen, nitrogen, or sulfur, wherein Cy^(A) is substituted with    0-3 R^(A) groups.    14. The compound of any one of the preceding embodiments, wherein    Cy^(A) is a 6-membered heteroarylene having 1 nitrogen, wherein    Cy^(A) is substituted with 0-3 R^(A) groups.    15. The compound of any one of the preceding embodiments, wherein    Cy^(A) is selected from either:

wherein * represents to point of attachment to L.16. The compound of any one of the preceding embodiments, wherein Cy^(A)is a 7- to 10-membered bicyclic heteroarylene having 1-4 heteroatomsselected from oxygen, nitrogen, or sulfur wherein Cy^(A) is substitutedwith 0-4 R^(A) groups.17. The compound of any one of the preceding embodiments, wherein Cy^(A)is a 9-membered bicyclic heteroarylene having 2 nitrogens wherein Cy^(A)is substituted with 0-4 R^(A) groups.18. The compound of any one of the preceding embodiments, wherein Cy^(A)is a pyrrolopyridinediyl substituted with 0-4 R^(A) groups.19. The compound of any one of the preceding embodiments, wherein Cy^(A)is a 5-membered heteroarylene having 1-4 heteroatoms selected fromoxygen, nitrogen, or sulfur, wherein Cy^(A) is substituted with 0-2R^(A) groups.20. The compound of any one of the preceding embodiments, wherein Cy^(A)is selected from the group consisting of: pyrrolediyl substituted with0-3 R^(A) groups, pyrazolediyl substituted with 0-2 R^(A) groups,triazolediyl substituted with 0-1 R^(A) groups, thiazolediyl substitutedwith 0-1 R^(A) groups, imidazolediyl substituted with 0-2 R^(A) groups,oxazolediyl substituted with 0-1 R^(A) groups, isoxazolediyl substitutedwith 0-1 R^(A) groups, unsubstituted tetrazolediyl, unsubstitutedoxadiazolediyl, and unsubstituted thiadiazolediyl.21. The compound of any one of the preceding embodiments, wherein Cy^(A)is selected from the group consisting of:

wherein * represents to point of attachment to L.22. The compound of any one of the preceding embodiments, wherein Cy^(A)is a 5-membered heteroarylene having 1-4 heteroatoms selected fromoxygen or nitrogen.23. The compound of any one of the preceding embodiments, wherein Cy^(A)is a 5-membered heteroarylene having 1-4 nitrogens.24. The compound of any one of the preceding embodiments, wherein Cy^(A)is a 5-membered heteroarylene having 1-4 nitrogen, wherein when Cy^(A)comprises 3 nitrogen, it is not a a 1,2,4, triazolediyl.25. The compound of any one of the preceding embodiments, wherein Cy^(A)is selected from the group consisting of:

wherein * represents to point of attachment to L.26. The compound of any one of the preceding embodiments, wherein thecompound is of Formula (III-a) through (III-d):

or a pharmaceutically acceptable salt thereof,wherein:

-   each R^(A) is independently selected from halogen, —CN, —C(R)═N(R),    —C(O)R, —C(O)₂R, —C(O)N(R)₂, —NO₂, —N(R)—N(R)₂, —N(R)₂, —N(R)C(O)R,    —N(R)C(O)₂R, —N(R)C(O)N(R)₂, —N(R)S(O)₂R, —OR, —OC(O)R, —OC(O)N(R)₂,    —SR, —S(O)R, —S(O)₂R, —S(O)N(R)₂, —S(O)₂N(R)₂, or an optionally    substituted group selected from C₁₋₆ aliphatic, phenyl, 5- to    6-membered heteroaryl having 1-4 heteroatoms selected from oxygen,    nitrogen, or sulfur, 3- to 7-membered saturated or partially    unsaturated monocyclic carbocyclyl, and 3- to 7-membered saturated    or partially unsaturated monocyclic heterocyclyl having 1-2    heteroatoms selected from oxygen, nitrogen, or sulfur;-   Cy^(B) is selected from 3- to 7-membered saturated or partially    unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected    from oxygen, nitrogen, or sulfur, 5- to 6-membered heteroaryl having    1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 7- to    10-membered saturated or partially unsaturated bicyclic heterocyclyl    having 1-5 heteroatoms selected from oxygen, nitrogen, or sulfur,    and 7- to 10-membered bicyclic heteroaryl having 1-5 heteroatoms    selected from oxygen, nitrogen, or sulfur, wherein Cy^(B) is    substituted with 0-5 R^(B) groups;-   each R^(B) is independently selected from halogen, —CN, —C(R)═N(R),    —C(O)R, —C(O)₂R, —C(O)N(R)₂, —NO₂, —N(R)—N(R)₂, —N(R)₂, —N(R)C(O)R,    —N(R)C(O)₂R, —N(R)C(O)N(R)₂, —N(R)S(O)₂R, —OR, —OC(O)R, —OC(O)N(R)₂,    —SR, —S(O)R, —S(O)₂R, —S(O)N(R)₂, —S(O)₂N(R)₂, or an optionally    substituted group selected from C₁₋₆ aliphatic, phenyl, 5- to    6-membered heteroaryl having 1-4 heteroatoms selected from oxygen,    nitrogen, or sulfur, 3- to 7-membered saturated or partially    unsaturated monocyclic carbocyclyl, and 3- to 7-membered saturated    or partially unsaturated monocyclic heterocyclyl having 1-2    heteroatoms selected from oxygen, nitrogen, or sulfur;-   R¹ and R² are independently selected from hydrogen and C₁₋₆    aliphatic;-   R⁶ and R⁷ are independently selected from hydrogen, halogen, —CN,    —C(R)═N(R), —C(O)R, —C(O)₂R, —C(O)N(R)₂, —NO₂, —N(R)—N(R)₂, —N(R)₂,    —N(R)C(O)R, —N(R)C(O)₂R, —N(R)C(O)N(R)₂, —N(R)S(O)₂R, —OR, —OC(O)R,    —OC(O)N(R)₂, —SR, —S(O)R, —S(O)₂R, —S(O)N(R)₂, —S(O)₂N(R)₂, or an    optionally substituted group selected from C₁₋₆ aliphatic, phenyl,    5- to 6-membered heteroaryl having 1-4 heteroatoms selected from    oxygen, nitrogen, or sulfur, 3- to 7-membered saturated or partially    unsaturated monocyclic carbocyclyl, and 3- to 7-membered saturated    or partially unsaturated monocyclic heterocyclyl having 1-2    heteroatoms selected from oxygen, nitrogen, or sulfur; and-   each R is independently hydrogen, —CN, or an optionally substituted    group selected from C₁₋₆ aliphatic, phenyl, 5- to 6-membered    heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or    sulfur, 3- to 7-membered saturated or partially unsaturated    monocyclic carbocyclyl, and 3- to 7-membered saturated or partially    unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected    from oxygen, nitrogen, or sulfur;-   or two R groups on the same carbon or nitrogen are taken together    with their intervening atoms to form a ring selected from 3- to    7-membered saturated or partially unsaturated monocyclic ring having    0-2 heteroatoms selected from oxygen, nitrogen, or sulfur, and 5- to    6-membered heteroaryl having 1-4 heteroatoms selected from oxygen,    nitrogen, or sulfur.    27. The compound of any one of the preceding embodiments, wherein    Cy^(B) is selected from phenyl, 7- to 10-membered saturated or    partially unsaturated bicyclic heterocyclyl having 1-5 heteroatoms    selected from oxygen, nitrogen, or sulfur, and 7- to 10-membered    bicyclic heteroaryl having 1-5 heteroatoms selected from oxygen,    nitrogen, or sulfur, wherein Cy^(B) is substituted with 0-5 R^(B)    groups.    28. The compound of any one of the preceding embodiments, wherein    Cy^(B) is a 7- to 10-membered bicyclic heteroaryl having 1-5    heteroatoms selected from oxygen, nitrogen, or sulfur, wherein    Cy^(B) is substituted with 0-5 R^(B) groups.    29. The compound of any one of the preceding embodiments, wherein    Cy^(B) is a 10-membered bicyclic heteroaryl having 1-5 heteroatoms    selected from oxygen, nitrogen, or sulfur, wherein Cy^(B) is    substituted with 0-5 R^(B) groups.    30. The compound of any one of the preceding embodiments, wherein    Cy^(B) is a 10-membered bicyclic heteroaryl having 1 nitrogen,    wherein Cy^(B) is substituted with 0-5 R^(B) groups.    31. The compound of any one of the preceding embodiments, wherein    Cy^(B) is selected from the group consisting of: quinolonyl group    substituted with 0-5 R^(B) groups and quinoxalinyl group substituted    with 0-5 R^(B) groups.    32. The compound of any one of the preceding embodiments, wherein    Cy^(B) is selected from the group consisting of:

33. The compound of any one of the preceding embodiments, wherein Cy^(B)is a 9-membered bicyclic heteroaryl having 1-5 heteroatoms selected fromoxygen, nitrogen, or sulfur, wherein Cy^(B) is substituted with 0-5R^(B) groups.34. The compound of any one of the preceding embodiments, wherein Cy^(B)is

wherein:

-   W¹, W², W³, and W⁴ are independently selected from carbon and    nitrogen;-   R¹⁰, R¹¹, R¹², R¹³, and R¹⁴ are each optionally present when    attached to a carbon atom, and if present correspond to an    occurrence of R^(B) independently selected from halogen, —CN,    —C(R)═N(R), —C(O)R, —C(O)₂R, —C(O)N(R)₂, —NO₂, —N(R)—N(R)₂, —N(R)₂,    —N(R)C(O)R, —N(R)C(O)₂R, —N(R)C(O)N(R)₂, —N(R)S(O)₂R, —OR, —OC(O)R,    —OC(O)N(R)₂, —SR, —S(O)R, —S(O)₂R, —S(O)N(R)₂, —S(O)₂N(R)₂, or an    optionally substituted group selected from C₁₋₆ aliphatic, phenyl,    5- to 6-membered heteroaryl having 1-4 heteroatoms selected from    oxygen, nitrogen, or sulfur, 3- to 7-membered saturated or partially    unsaturated monocyclic carbocyclyl, and 3- to 7-membered saturated    or partially unsaturated monocyclic heterocyclyl having 1-2    heteroatoms selected from oxygen, nitrogen, or sulfur; and-   each R is independently hydrogen, —CN, or an optionally substituted    group selected from C₁₋₆ aliphatic, phenyl, 5- to 6-membered    heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or    sulfur, 3- to 7-membered saturated or partially unsaturated    monocyclic carbocyclyl, and 3- to 7-membered saturated or partially    unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected    from oxygen, nitrogen, or sulfur;-   or two R groups on the same carbon or nitrogen are taken together    with their intervening atoms to form a ring selected from 3- to    7-membered saturated or partially unsaturated monocyclic ring having    0-2 heteroatoms selected from oxygen, nitrogen, or sulfur, and 5- to    6-membered heteroaryl having 1-4 heteroatoms selected from oxygen,    nitrogen, or sulfur.    35. The compound of any one of the preceding embodiments, W⁴ is    carbon.    36. The compound of any one of the preceding embodiments, W⁴ is    nitrogen.    37. The compound of any one of the preceding embodiments, W¹ is    nitrogen and W², W³ and W⁴ are carbon.    38. The compound of any one of the preceding embodiments, W² is    nitrogen and W¹, W³ and W⁴ are carbon.    39. The compound of any one of the preceding embodiments, nitrogen    and W¹ and W⁴ are carbon.    40. The compound of any one of the preceding embodiments, W² and W⁴    are nitrogen and W¹ and W³ are carbon.    41. The compound of any one of the preceding embodiments, wherein    Cy^(B) is selected from the group consisting of imidazopyridinyl    substituted with 0-5 R^(B) groups, pyrazolopyridinyl substituted    with 0-5 R^(B) groups, pyrrolopyridinyl substituted with 0-4 R^(B)    groups, triazolopyridinyl substituted with 0-4 R^(B) groups,    imidazopyrimidinyl substituted with 0-4 R^(B) groups,    imidazopyridazinyl substituted with 0-4 R^(B) groups, indolizinyl    substituted with 0-5 R^(B) groups, and pyrazolopyrimidinyl    substituted with 0-4 R^(B) groups.    42. The compound of any one of the preceding embodiments, wherein    Cy^(B) is selected from the group consisting of:

43. The compound of any one of the preceding embodiments, wherein Cy^(B)is

wherein:

-   W² is selected from carbon, nitrogen, oxygen, and sulfur;-   W¹, W³, and W⁴ are independently selected from carbon and nitrogen;-   R¹⁰, R¹¹, R¹², R¹³, and R¹⁴ are each optionally present when    attached to a carbon atom, and if present correspond to an    occurrence of R^(B) independently selected from halogen, —CN,    —C(R)═N(R), —C(O)R, —C(O)₂R, —C(O)N(R)₂, —NO₂, —N(R)—N(R)₂, —N(R)₂,    —N(R)C(O)R, —N(R)C(O)₂R, —N(R)C(O)N(R)₂, —N(R)S(O)₂R, —OR, —OC(O)R,    —OC(O)N(R)₂, —SR, —S(O)R, —S(O)₂R, —S(O)N(R)₂, —S(O)₂N(R)₂, or an    optionally substituted group selected from C₁₋₆ aliphatic, phenyl,    5- to 6-membered heteroaryl having 1-4 heteroatoms selected from    oxygen, nitrogen, or sulfur, 3- to 7-membered saturated or partially    unsaturated monocyclic carbocyclyl, and 3- to 7-membered saturated    or partially unsaturated monocyclic heterocyclyl having 1-2    heteroatoms selected from oxygen, nitrogen, or sulfur; and-   each R is independently hydrogen, —CN, or an optionally substituted    group selected from C₁₋₆ aliphatic, phenyl, 5- to 6-membered    heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or    sulfur, 3- to 7-membered saturated or partially unsaturated    monocyclic carbocyclyl, and 3- to 7-membered saturated or partially    unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected    from oxygen, nitrogen, or sulfur;-   or two R groups on the same carbon or nitrogen are taken together    with their intervening atoms to form a ring selected from 3- to    7-membered saturated or partially unsaturated monocyclic ring having    0-2 heteroatoms selected from oxygen, nitrogen, or sulfur, and 5- to    6-membered heteroaryl having 1-4 heteroatoms selected from oxygen,    nitrogen, or sulfur.    44. The compound of any one of the preceding embodiments, wherein    Cy^(B) is selected from the group consisting of a indolyl    substituted with 0-5 R^(B) groups, a benzofuranyl substituted with    0-5 R^(B) groups, a benzimidazolyl substituted with 0-4 R^(B)    groups, and a thienopyridinyl substituted with 0-4 R^(B) groups.    45. The compound of any one of the preceding embodiments, wherein    Cy^(B) is selected from the group consisting of:

46. The compound of any one of the preceding embodiments, wherein eachR^(A) is independently selected from an optionally substituted groupselected from C₁₋₆ aliphatic, 3- to 7-membered saturated or partiallyunsaturated monocyclic carbocyclyl, and 3- to 7-membered saturated orpartially unsaturated monocyclic heterocyclyl having 1-2 heteroatomsselected from oxygen, nitrogen, or sulfur.47. The compound of any one of the preceding embodiments, whereinsubstituents on an optionally substituted R^(A) group are independentlyhalogen, (CH₂)₀₋₄R^(∘), —(CH₂)₀₋₄OR^(∘); and —(CH₂)₀₋₄C(O)OR^(∘),wherein each R^(∘) is independently hydrogen, C₁₋₆ aliphatic, or a 5-6membered saturated, partially unsaturated, or aryl ring having 0-4heteroatoms independently selected from nitrogen, oxygen, or sulfur.48. The compound of any one of the preceding embodiments, wherein asingle instance of R^(A) is C₁₋₆ aliphatic substituted with halogen.49. The compound of any one of the preceding embodiments, wherein asingle instance of R^(A) is C₁₋₆ aliphatic substituted with—(CH₂)₀₋₄OR^(∘), wherein R^(∘) is hydrogen or C₁₋₆ aliphatic.50. The compound of any one of the preceding embodiments, wherein asingle instance of R^(A) is C₁₋₆ aliphatic substituted with—(CH₂)₀₋₄C(O)OR^(∘), wherein R^(∘) is hydrogen or C₁₋₆ aliphatic.51. The compound of any one of the preceding embodiments, wherein asingle instance of R^(A) is C₁₋₆ aliphatic is substituted with 5-6membered saturated, partially unsaturated, or aryl ring having 0-4heteroatoms independently selected from nitrogen, oxygen, or sulfur.52. The compound of any one of the preceding embodiments, wherein asingle instance of R^(A) is optionally substituted 3- to 7-memberedsaturated or partially unsaturated monocyclic carbocyclyl. In someembodiments, a single instance of R^(A) is optionally substitutedcyclopropyl. In some embodiments, a single instance of R^(A) iscyclopropyl substituted with —(CH₂)₀₋₄C(O)OR^(∘) and R^(∘) is hydrogenor C₁₋₆ aliphatic.53. The compound of any one of the preceding embodiments, wherein R⁵,R⁶, R⁷, R⁸, and R⁹ are independently selected from hydrogen, halogen,—CN, —N(R)₂, —OR, or an optionally substituted group selected from C₁₋₄aliphatic, 3- to 7-membered saturated or partially unsaturatedmonocyclic carbocyclyl, wherein each R is independently hydrogen or C₁₋₆aliphatic.54. The compound of any one of the preceding embodiments, wherein R⁵,R⁶, and R⁹ are hydrogen.55. The compound of any one of the preceding embodiments, wherein R⁶ isselected from hydrogen or halogen.56. The compound of any one of the preceding embodiments, wherein R ishydrogen.57. The compound of any one of the preceding embodiments, wherein R ishalogen.58. The compound of any one of the preceding embodiments, wherein R⁶ is—F.59. The compound of any one of the preceding embodiments, wherein R⁶ is—Cl.60. The compound of any one of the preceding embodiments, wherein R is—Br.61. The compound of any one of the preceding embodiments, wherein R⁷ isselected from halogen or an optionally substituted C₁₋₆ aliphatic.62. The compound of any one of the preceding embodiments, wherein R⁷ ishalogen.63. The compound of any one of the preceding embodiments, wherein R⁷ is—F.64. The compound of any one of the preceding embodiments, wherein R⁷ is—Cl.65. The compound of any one of the preceding embodiments, wherein R⁷ is—Br.66. The compound of any one of the preceding embodiments, wherein R⁷ isoptionally substituted C₁₋₆ aliphatic.67. The compound of any one of the preceding embodiments, wherein R¹¹ isoptionally present, and if present is independently selected fromhalogen, —CN, —C(R)═N(R), —C(O)R, —

C(O)N(R)₂, —NO₂, —N(R)—N(R)₂, —N(R)₂, —N(R)C(O)R, —N(R)C(O)₂R,—N(R)C(O)N(R)₂, —N(R)S(O)₂R, —OR, —OC(O)R, —OC(O)N(R)₂, —SR, —S(O)R,—S(O)₂R, —S(O)N(R)₂, —S(O)₂N(R)₂, or an optionally substituted groupselected from C₁₋₆ aliphatic, phenyl, 5- to 6-membered heteroaryl having1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 3- to7-membered saturated or partially unsaturated monocyclic carbocyclyl,and 3- to 7-membered saturated or partially unsaturated monocyclicheterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, orsulfur.

68. The compound of any one of the preceding embodiments, wherein R¹¹ isselected from —CN, —C(R)═N(R), —C(O)R, —C(O)₂R, —C(O)N(R)₂, —NO₂,—N(R)—N(R)₂, —N(R)₂, —N(R)C(O)R, —N(R)C(O)₂R, —N(R)C(O)N(R)₂,—N(R)S(O)₂R, —OR, —OC(O)R, —OC(O)N(R)₂, —SR, —S(O)R, —S(O)₂R,—S(O)N(R)₂, —S(O)₂N(R)₂, or an optionally substituted group selectedfrom phenyl, 5- to 6-membered heteroaryl having 1-4 heteroatoms selectedfrom oxygen, nitrogen, or sulfur, 3- to 7-membered saturated orpartially unsaturated monocyclic carbocyclyl, and 3- to 7-memberedsaturated or partially unsaturated monocyclic heterocyclyl having 1-2heteroatoms selected from oxygen, nitrogen, or sulfur.69. The compound of any one of the preceding embodiments, wherein R¹¹ isselected from halogen, optionally substituted C₁₋₆ aliphatic, andoptionally substituted 3- to 7-membered saturated or partiallyunsaturated monocyclic carbocyclyl.70. The compound of any one of the preceding embodiments, wherein R¹¹ ishalogen.71. The compound of any one of the preceding embodiments, wherein R¹¹ isoptionally substituted C₁₋₄ aliphatic.72. The compound of any one of the preceding embodiments, wherein R¹¹ isan optionally substituted 3- to 7-membered saturated or partiallyunsaturated monocyclic carbocyclyl.73. The compound of any one of the preceding embodiments, wherein R¹¹ isan optionally substituted 3- or 5-7-membered saturated or partiallyunsaturated monocyclic carbocyclyl.74. The compound of any one of the preceding embodiments, wherein R¹¹ isan optionally substituted cyclopropyl.75. The compound of any one of the preceding embodiments, wherein thecompound is any one of compounds I-1 through I-303, or apharmaceutically acceptable salt thereof.76. A pharmaceutical composition comprising any one of the precedingcompounds.77. The pharmaceutical composition comprising any one of the precedingcompounds further comprising a pharmaceutically acceptable excipient.78. The pharmaceutical composition of any one of embodiments 76-77,wherein the composition is suitable for oral administration.79. The pharmaceutical composition of any one of embodiments 76-77,wherein the composition is suitable for administration by injection.80. A method of treating a plasma kallikrein-mediated disease ordisorder using a compound or composition of any one of the precedingembodiments.81. The method of embodiment 80, wherein the disease or disorder ishereditary angioedema or diabetic macular edema.82. A method of treating hereditary angioedema or diabetic macular edemacomprising administering to a patient in need thereof a compound of anyone of the preceding embodiments.

The following numbered embodiments, while non-limiting, are alsoexemplary of certain aspects of the present disclosure:

83. A compound of Formula (I):

or a pharmaceutically acceptable salt thereof,wherein:

-   Cy^(A) is selected from 3- to 7-membered saturated or partially    unsaturated monocyclic heterocyclyenel having 1-2 heteroatoms    selected from oxygen, nitrogen, or sulfur, 5- to 6-membered    heteroarylene having 1-4 heteroatoms selected from oxygen, nitrogen,    or sulfur, 7- to 10-membered saturated or partially unsaturated    bicyclic heterocyclylene having 1-4 heteroatoms selected from    oxygen, nitrogen, or sulfur, and 7- to 10-membered bicyclic    heteroarylene having 1-4 heteroatoms selected from oxygen, nitrogen,    or sulfur, wherein Cy^(A) is substituted with 0-4 R^(A) groups;-   each R^(A) is independently selected from halogen, —CN, —C(R)═N(R),    —C(O)R, —C(O)₂R, —C(O)N(R)₂, —NO₂, —N(R)—N(R)₂, —N(R)₂, —N(R)C(O)R,    —N(R)C(O)₂R, —N(R)C(O)N(R)₂, —N(R)S(O)₂R, —OR, —OC(O)R, —OC(O)N(R)₂,    —SR, —S(O)R, —S(O)₂R, —S(O)N(R)₂, —S(O)₂N(R)₂, or an optionally    substituted group selected from C₁₋₆ aliphatic, phenyl, 5- to    6-membered heteroaryl having 1-4 heteroatoms selected from oxygen,    nitrogen, or sulfur, 3- to 7-membered saturated or partially    unsaturated monocyclic carbocyclyl, and 3- to 7-membered saturated    or partially unsaturated monocyclic heterocyclyl having 1-2    heteroatoms selected from oxygen, nitrogen, or sulfur;-   Cy^(B) is selected from 3- to 7-membered saturated or partially    unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected    from oxygen, nitrogen, or sulfur, 5- to 6-membered heteroaryl having    1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 7- to    10-membered saturated or partially unsaturated bicyclic heterocyclyl    having 1-5 heteroatoms selected from oxygen, nitrogen, or sulfur,    and 7- to 10-membered bicyclic heteroaryl having 1-5 heteroatoms    selected from oxygen, nitrogen, or sulfur, wherein Cy^(B) is    substituted with 0-5 R^(B) groups;-   each R^(B) is independently selected from halogen, —CN, —C(R)═N(R),    —C(O)R, —C(O)₂R, —C(O)N(R)₂, —NO₂, —N(R)—N(R)₂, —N(R)₂, —N(R)C(O)R,    —N(R)C(O)₂R, —N(R)C(O)N(R)₂, —N(R)S(O)₂R, —OR, —OC(O)R, —OC(O)N(R)₂,    —SR, —S(O)R, —S(O)₂R, —S(O)N(R)₂, —S(O)₂N(R)₂, or an optionally    substituted group selected from C₁₋₆ aliphatic, phenyl, 5- to    6-membered heteroaryl having 1-4 heteroatoms selected from oxygen,    nitrogen, or sulfur, 3- to 7-membered saturated or partially    unsaturated monocyclic carbocyclyl, and 3- to 7-membered saturated    or partially unsaturated monocyclic heterocyclyl having 1-2    heteroatoms selected from oxygen, nitrogen, or sulfur;-   L is selected from -QC(R)₂—, —C(R)₂Q-, -QC(Q)-, —C(Q)Q-,    —C(R)₂QC(O)—, and —C(O)QC(R)₂—, wherein each Q is independently a    monovalent or divalent group as valency allows, selected from the    group consisting of O, N(R), or (S);-   R¹, R², R³, and R⁴ are independently selected from hydrogen and C₁₋₆    aliphatic;-   R⁵, R⁶, R⁷, R⁸, and R⁹ are independently selected from hydrogen,    halogen, —CN, —C(R)═N(R), —C(O)R, —C(O)₂R, —C(O)N(R)₂, —NO₂,    —N(R)—N(R)₂, —N(R)₂, —N(R)C(O)R, —N(R)C(O)₂R, —N(R)C(O)N(R)₂,    —N(R)S(O)₂R, —OR, —OC(O)R, —OC(O)N(R)₂, —SR, —S(O)R, —S(O)₂R,    —S(O)N(R)₂, —S(O)₂N(R)₂, or an optionally substituted group selected    from C₁₋₆ aliphatic, phenyl, 5- to 6-membered heteroaryl having 1-4    heteroatoms selected from oxygen, nitrogen, or sulfur, 3- to    7-membered saturated or partially unsaturated monocyclic    carbocyclyl, and 3- to 7-membered saturated or partially unsaturated    monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen,    nitrogen, or sulfur; and-   each R is independently hydrogen, —CN, or an optionally substituted    group selected from C₁₋₆ aliphatic, phenyl, 5- to 6-membered    heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or    sulfur, 3- to 7-membered saturated or partially unsaturated    monocyclic carbocyclyl, and 3- to 7-membered saturated or partially    unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected    from oxygen, nitrogen, or sulfur;-   or two R groups on the same carbon or nitrogen are taken together    with their intervening atoms to form a ring selected from 3- to    7-membered saturated or partially unsaturated monocyclic ring having    0-2 heteroatoms selected from oxygen, nitrogen, or sulfur, and 5- to    6-membered heteroaryl having 1-4 heteroatoms selected from oxygen,    nitrogen, or sulfur;-   with the proviso that the compound is other than    N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-2-((3-chloroquinolin-6-yl)methyl)isonicotinamide.    84. The compound of embodiment 83, wherein the compound is of    Formula (II):

or a pharmaceutically acceptable salt thereof.85. The compound of any one of the preceding embodiments, with theproviso that Cy^(A) is a group other than pyridinediyl and the compoundis other thanN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-2-((3-chloroquinolin-6-yl)methyl)isonicotinamide.86. The compound of any one of the preceding embodiments, wherein Cy^(A)is selected from 5- to 6-membered heteroaryl having 1-4 heteroatomsselected from oxygen, nitrogen, or sulfur, and 7- to 10-memberedbicyclic heteroaryl having 1-4 heteroatoms selected from oxygen,nitrogen, or sulfur wherein Cy^(A) is substituted with 0-4 R^(A) groups.87. The compound of any one of the preceding embodiments, wherein Cy^(A)is selected from the group consisting of pyrrolopyridinediyl substitutedwith 0-4 R^(A), pyrazolediyl substituted with 0-2 R^(A) groups,triazolediyl substituted with 0-1 R^(A) groups, thiazolediyl substitutedwith 0-1 R^(A)(R^(A) (groups, imidazolediyl substituted with 0-2 R^(A)groups, oxazolediyl substituted with 0-1 R^(A) groups, isoxazolediylsubstituted with 0-1 R^(A) groups, unsubstituted tetrazolediyl,unsubstituted oxadiazolediyl, and unsubstituted thiadiazolediyl.88. The compound of any one of the preceding embodiments, wherein Cy^(A)is selected from the group consisting of:

wherein * represents to point of attachment to L.89. The compound of any one of the preceding embodiments, wherein thecompound has a structure selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.90. The compound of any one of the preceding embodiments, wherein Cy^(B)is a 7- to 10-membered bicyclic heteroaryl having 1-5 heteroatomsselected from oxygen, nitrogen, or sulfur, wherein Cy^(B) is substitutedwith 0-5 R^(B) groups.91. The compound of any one of the preceding embodiments, wherein Cy^(B)is

wherein:W¹, W², W³, and W⁴ are independently selected from carbon and nitrogen;

-   R¹⁰, R¹¹, R¹², R¹³, and R¹⁴ are each optionally present when    attached to a carbon atom, and if present correspond to an    occurrence of R^(B) independently selected from halogen, —CN,    —C(R)═N(R), —C(O)R, —C(O)₂R, —C(O)N(R)₂, —NO₂, —N(R)—N(R)₂, —N(R)₂,    —N(R)C(O)R, —N(R)C(O)₂R, —N(R)C(O)N(R)₂, —N(R)S(O)₂R, —OR, —OC(O)R,    —OC(O)N(R)₂, —SR, —S(O)R, —S(O)₂R, —S(O)N(R)₂, —S(O)₂N(R)₂, or an    optionally substituted group selected from C₁₋₆ aliphatic, phenyl,    5- to 6-membered heteroaryl having 1-4 heteroatoms selected from    oxygen, nitrogen, or sulfur, 3- to 7-membered saturated or partially    unsaturated monocyclic carbocyclyl, and 3- to 7-membered saturated    or partially unsaturated monocyclic heterocyclyl having 1-2    heteroatoms selected from oxygen, nitrogen, or sulfur; and-   each R is independently hydrogen, —CN, or an optionally substituted    group selected from C₁₋₆ aliphatic, phenyl, 5- to 6-membered    heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or    sulfur, 3- to 7-membered saturated or partially unsaturated    monocyclic carbocyclyl, and 3- to 7-membered saturated or partially    unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected    from oxygen, nitrogen, or sulfur;-   or two R groups on the same carbon or nitrogen are taken together    with their intervening atoms to form a ring selected from 3- to    7-membered saturated or partially unsaturated monocyclic ring having    0-2 heteroatoms selected from oxygen, nitrogen, or sulfur, and 5- to    6-membered heteroaryl having 1-4 heteroatoms selected from oxygen,    nitrogen, or sulfur.    92. The compound of any one of the preceding embodiments, wherein    Cy^(B) is selected from the group consisting of imidazopyridinyl    substituted with 0-5 R^(B) groups, pyrazolopyridinyl substituted    with 0-5 R^(B) groups, pyrrolopyridinyl substituted with 0-4 R^(B)    groups, triazolopyridinyl substituted with 0-4 R^(B) groups,    imidazopyrimidinyl substituted with 0-4 R^(B) groups,    imidazopyridazinyl substituted with 0-4 R^(B) groups, indolizinyl    substituted with 0-5 R^(B) groups, and pyrazolopyrimidinyl    substituted with 0-4 R^(B) groups.    93. The compound of any one of the preceding embodiments, wherein    Cy^(B) is selected from the group consisting of:

94. The compound of any one of embodiments 83-90, wherein Cy^(B) is

wherein:

-   W² is selected from carbon, nitrogen, oxygen, and sulfur;-   W¹, W³, and W⁴ are independently selected from carbon and nitrogen;-   R¹⁰, R¹¹, R¹², R¹³, and R¹⁴ are each optionally present when    attached to a carbon atom, and if present correspond to an    occurrence of R^(B) independently selected from halogen, —CN,    —C(R)═N(R), —C(O)R, —C(O)₂R, —C(O)N(R)₂, —NO₂, —N(R)—N(R)₂, —N(R)₂,    —N(R)C(O)R, —N(R)C(O)₂R, —N(R)C(O)N(R)₂, —N(R)S(O)₂R, —OR, —OC(O)R,    —OC(O)N(R)₂, —SR, —S(O)R, —S(O)₂R, —S(O)N(R)₂, —S(O)₂N(R)₂, or an    optionally substituted group selected from C₁₋₆ aliphatic, phenyl,    5- to 6-membered heteroaryl having 1-4 heteroatoms selected from    oxygen, nitrogen, or sulfur, 3- to 7-membered saturated or partially    unsaturated monocyclic carbocyclyl, and 3- to 7-membered saturated    or partially unsaturated monocyclic heterocyclyl having 1-2    heteroatoms selected from oxygen, nitrogen, or sulfur; and-   each R is independently hydrogen, —CN, or an optionally substituted    group selected from C₁₋₆ aliphatic, phenyl, 5- to 6-membered    heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or    sulfur, 3- to 7-membered saturated or partially unsaturated    monocyclic carbocyclyl, and 3- to 7-membered saturated or partially    unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected    from oxygen, nitrogen, or sulfur;-   or two R groups on the same carbon or nitrogen are taken together    with their intervening atoms to form a ring selected from 3- to    7-membered saturated or partially unsaturated monocyclic ring having    0-2 heteroatoms selected from oxygen, nitrogen, or sulfur, and 5- to    6-membered heteroaryl having 1-4 heteroatoms selected from oxygen,    nitrogen, or sulfur.    95. The compound of any one of embodiments 83-90 and 94, wherein    Cy^(B) is selected from the group consisting of a indolyl    substituted with 0-5 R^(B) groups, a benzofuranyl substituted with    0-5 R^(B) groups, a pyrazolopyrimidinyl substituted with 0-4 R^(B)    groups, a benzimidazolyl substituted with 0-4 R^(B) groups, and a    thienopyridinyl substituted with 0-4 R^(B) groups.    96. The compound of any one of embodiments 83-90 and 94-95, wherein    Cy^(B) is selected from the group consisting of:

97. The compound of any one of embodiments 83-90, wherein Cy^(B) is aquinolondiyl group substituted with 0-5 R^(B) groups.98. The compound of embodiment any one of embodiments 83-90 and 97,wherein Cy^(B) is

99. The compound of any one of the preceding embodiments, wherein L is—N(H)C(O)— or embodiments, L is —C(O)N(H)—.

100. The compound of any one of the preceding embodiments, wherein R⁶ ishalogen.101. The compound of embodiment 91 or 94, wherein R¹¹ is selected fromhalogen, optionally substituted C₁₋₆ aliphatic, and optionallysubstituted 3- to 7-membered saturated or partially unsaturatedmonocyclic carbocyclyl.102. The compound of embodiment 91 or 94, wherein R¹¹ is an optionallysubstituted cyclopropyl.103. A pharmaceutical composition comprising any one of the precedingcompounds.104. The pharmaceutical composition of embodiment 103 further comprisinga pharmaceutically acceptable excipient.105. The pharmaceutical composition of any one of embodiments 103-104,wherein the composition is suitable for oral administration.106. The pharmaceutical composition of any one of embodiments 103-104,wherein the composition is suitable for administration by injection.107. A method of treating a plasma kallikrein-mediated disease ordisorder using a compound any one of embodiments 83-102 or compositionaccording to of any one of embodiments 103-106.108. The method of embodiment 27, wherein the disease or disorder ishereditary angioedema or diabetic macular edema.109. A method of treating hereditary angioedema or diabetic macularedema comprising administering to a patient in need thereof a compoundof any one of embodiments 83-102 or composition according to of any oneof embodiments 103-106.

IV. EXAMPLES Example 1

Synthesis of Methyl1-((3-chloroquinolin-6-yl)methyl)-1H-pyrazole-4-carboxylate

A mixture of 3-chloro-6-(chloromethyl)quinoline (200 mg, 0.95 mmol),methyl 1H-pyrazole-4-carboxylate (1.2 g, 0.95 mmol) and Cs₂CO₃ (930 mg,2.85 mmol) in McCN (5 mL) was stirred at 70° C. for 1 h. Water was addedand extracted with EtOAc, the combined organic layers were concentratedand purified by silcial gel column (EA/PE=1/10) to give methyl1-((3-chloroquinolin-6-yl)methyl)-1H-pyrazole-4-carboxylate (200 mg,yield: 78%) as a white solid. ESI-MS [M+H]⁺: 302.1.

Synthesis of 1-((3-chloroquinolin-6-yl)methyl)-1H-pyrazole-4-carboxylicAcid

A mixture of methyl1-((3-chloroquinolin-6-yl)methyl)-1H-pyrazole-4-carboxylate (200 mg,0.66 mmol) and LiOH (158 mg, 6.6 mmol) in THF (10 mL) and H₂O (5 mL) wasstirred at 100° C. for overnight. Water was added and the pH value ofthe mixture was adjusted to 4-5 by added 1 M HCl solution. The mixturewas then extracted with EtOAc (20 mL×3), the combined organic layerswere concentrated to give1-((3-chloroquinolin-6-yl)methyl)-1H-pyrazole-4-carboxylic acid (150 mg,yield: 72%) as a white solid, which was used into next step withoutfurther purification. ESI-MS [M+H]⁺: 288.0.

Synthesis ofN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((3-chloroquinolin-6-yl)methyl)-1H-pyrazole-4-carboxamide(I-1)

A mixture of 1-((3-chloroquinolin-6-yl)methyl)-1H-pyrazole-4-carboxylicacid (50 mg, 0.17 mmol), (7-chloroimidazo[1,5-a]pyridin-1-yl)methanamine(37 mg, 0.17 mmol), and HATU (98 mg, 0.06 mmol) and DIPEA (66 mg, 0.51mmol) in DMF (2 mL) was stirred at RT overnight. Water (10 mL) was addedand extracted with EtOAc (20 mL×3), the combined organic layers wereconcentrated and purified by prep-HPLC to giveN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((3-chloroquinolin-6-yl)methyl)-1H-pyrazole-4-carboxamide(17.3 mg, yield: 20%) as a white solid. ESI-MS [M+H]⁺: 451.1. Purity:99.49%. ¹H NMR (400 MHz, DMSO): δ 8.88 (d, J=2.2 Hz, 1H), 8.64-8.58 (m,2H), 8.36-8.31 (m, 3H), 8.03 (d, J=8.7 Hz, 1H), 7.94 (s, 1H), 7.80 (d,J=8.7 Hz, 2H), 7.65 (d, J=8.7 Hz, 1H), 6.67 (dd, J=7.4, 1.8 Hz, 1H),5.56 (s, 2H), 4.57 (d, J=5.4 Hz, 2H).

Example 2

Synthesis ofN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide

To a mixture of (7-chloroimidazo[1,5-a]pyridin-1-yl)methanaminehydrochloride (2.5 g, 11.52 mmol), 1H-pyrazole-4-carboxylic acid (920mg, 8.23 mmol), HATU (3.9 g, 10.29 mmol) in DMF (300 mL) was added DIPEA(7.3 mL, 41.14 mmol). The resulting reaction mixture was stirred at RTfor 14 h. The reaction was then concentrated to remove most of the DMF,and the residue was poured into H₂O (150 mL) and brown solid wasprecipitated out. The precipitate was filtered and the filtrated cakewas triturated with DCM and dried to give theN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide,which was used into next step without further purification (2 g, yield:88%). ESI-MS [M+H]⁺: 276.2.

Synthesis ofN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(I-2)

A mixture ofN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide(2 g, 7.27 mmol), 2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine(1.96 g, 9.45 mmol) and Cs₂CO₃ (7.1 g, 21.81 mmol) in DMF (50 mL) wasstirred at 50° C. for 14 h. H₂O (200 mL) was added, extracted with EtOAc(300 mL×3). The combined organic layers were washed with brine, driedover Na₂SO₄, concentrated in vacuo to give the crude, which was purifiedwith silica gel chromatography (DCM/MeOH=10/1) to give theN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamideas a white solid (1.5 g, yield: 46%). LCMS m/z: 446.1 [M+H]*,t_(R)=1.040 min, purity: 98.6% (214 nm), 97.4% (254 nm). ¹H NMR (400MHz, DMSO): δ 8.58 (t, J=5.7 Hz, 1H), 8.32-8.29 (m, 3H), 8.20 (s, 1H),7.85 (s, 1H), 7.78 (s, 1H), 7.71 (s, 1H), 7.39 (d, J=9.3 Hz, 1H),7.00-6.98 (m, 1H), 6.64 (dd, J=7.5, 2.0 Hz, 1H), 5.38 (s, 2H), 4.55 (d,J=5.7 Hz, 2H), 1.91 (ddd, J=13.5, 8.4, 5.1 Hz, 1H), 0.99-0.87 (m, 2H),0.77-0.61 (m, 2H).

Example 3

Synthesis ofN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-2-((3-chloroquinolin-6-yl)methyl)isonicotinamide(I-3)

To a solution of 2-((3-chloroquinolin-6-yl)methyl)isonicotinic acid (60mg, 0.20 mmol), (7-chloroimidazo[1,5-a]pyridin-1-yl)methanamine (44 mg,0.24 mmol) and HATU (115 mg, 0.30 mmol) in DMF (8 mL) was added DIPEA(77 mg, 0.60 mmol). The resulting reaction was stirred at RT for 12 h.H₂O (20 mL) was added, extracted with EtOAc (20 mL×3). The combinedorganic layers were washed with brine, dried over Na₂SO₄, concentratedin vacuo to give the crude, which was purified with prep-TLC(DCM/MeOH=10/1) to give theN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-2-((3-chloroquinolin-6-yl)methyl)isonicotinamide(20 mg, yield: 22%) as a white solid. ESI-MS [M+H]⁺: 462.0. Purity:98.3%. ¹H NMR (400 MHz, DMSO): δ 9.27-9.24 (m, 1H), 8.84-8.81 (m, 1H),8.62 (d, J=5.0 Hz, 1H), 8.51 (s, 1H), 8.38-8.26 (m, 2H), 7.97 (d, J=8.6Hz, 1H), 7.90-7.69 (m, 4H), 7.62 (d, J=4.7 Hz, 1H), 6.66 (d, J=7.4 Hz,1H), 4.64 (d, J=5.5 Hz, 2H), 4.35 (s, 2H).

Example 4

Synthesis of tert-butyl((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamate

A mixture of (7-chloroimidazo[1,5-a]pyridin-1-yl)methanamine (300 mg,1.65 mmol), Boc₂O (537 mg, 2.4 mmol) and DIPEA (1.06 g, 8.25 mmol) inDCM (40 mL) was stirred at RT for 12 h. The reaction was quenched withH₂O (50 mL), extracted with DCM (50 mL×2). The combined organic layerswere washed with brine, dried over Na₂SO₄, concentrated in vacuo to givethe crude, which was purified with silica gel chromatography (PE/EA=1/1)to give the tert-butyl((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamate (210 mg, yield:45%) as a yellow solid. ESI-MS [M+H]⁺: 282.2.

Synthesis of tert-butyl((7-methylimidazo[1,5-a]pyridin-1-yl)methyl)carbamate

A mixture of tert-butyl((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamate (210 mg, 0.75mmol), 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (188 mg, 1.5 mmol),Pd(PPh₃)₄ (87 mg, 0.075 mmol) and K₂CO₃ (310 mg, 2.25 mmol) indioxane/H₂O (10 mL/1 mL) in a sealed tube was stirred at 100° C. for 12h. H₂O (30 mL) was added to the reaction, extracted with EtOAc (30mL×3). The combined organic layers were washed with brine, dried overNa₂SO₄, concentrated in vacuo to give the crude, which was purified withsilica gel chromatography (EA/PE=1/1) to give the tert-butyl((7-methylimidazo[1,5-a]pyridin-1-yl)methyl)carbamate (150 mg, yield:77%) as a light yellow solid. ESI-MS [M+H]⁺: 262.3.

Synthesis of (7-methylimidazo[1,5-a]pyridin-1-yl)methanamineHydrochloride

To a solution of tert-butyl((7-methylimidazo[1,5-a]pyridin-1-yl)methyl)carbamate (150 mg, 0.57mmol) in MeOH (3 mL) was added HCl (4 M solution in MeOH, 3 mL). Theresulting reaction was stirred at RT for 2 h. The reaction wasconcentrated in vacuo to give the(7-methylimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride (95 mg,yield: 85%). ESI-MS [M+H]⁺: 162.2.

Synthesis of1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-((7-methylimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide(I-4)

To a solution of1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylicacid (136 mg, 0.48 mmol),(7-methylimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride (95 mg,0.48 mmol) and HATU (238 mg, 0.63 mmol) in DMF (15 mL) was added DIPEA(310 mg, 2.4 mmol). The resulting reaction was stirred at RT for 12 h.H₂O (25 mL) was added to the reaction, extracted with EtOAc (30 mL×3).The combined organic layers were washed with brine, dried over Na₂SO₄,concentrated in vacuo to give the crude, which was purified withprep-TLC (DCM/MeOH=10/1) to give the1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-((7-methylimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide(21 mg, yield: 10%) as a white solid. ESI-MS [M+H]⁺: 426.2. Purity:96.4%. ¹H NMR (400 MHz, DMSO): δ 8.47 (s, 1H), 8.39-8.04 (m, 5H), 7.86(s, 1H), 7.71 (s, 1H), 7.40-7.35 (m, 2H), 6.99 (d, J=9.1 Hz, 1H), 6.45(d, J=7.0 Hz, 1H), 5.38 (s, 2H), 4.54 (d, J=4.5 Hz, 2H), 2.20 (s, 3H),1.95-1.88 (m, 1H), 0.93-0.90 (m, 2H), 0.68-0.63 (m, 2H).

Example 5

Synthesis ofN-((7-bromoimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide.(I-5)

To a solution of1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylicacid (154 mg, 0.54 mmol), (7-bromoimidazo[1,5-a]pyridin-1-yl)methanamine(120 mg, 0.54 mmol) and HATU (310 mg, 0.82 mmol) in DMF (4 mL) was addedDIPEA (210 mg, 1.63 mmol). The resulting reaction was stirred at RT for12 h. H₂O (20 mL) was added, extracted with EtOAc (25 mL×3). Thecombined organic layers were washed with brine, dried over Na₂SO₄,concentered in vacuo to give the crude, which was purified with prep-TLC(DCM/MeOH=10/1) to give theN-((7-bromoimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(24 mg, yield: 9%) as a white solid. ESI-MS [M+H]⁺: 490.1. Purity:98.24%. ¹H NMR (400 MHz, DMSO): δ 8.57 (t, J=8.0 Hz, 1H), 8.32 (d, J=4.2Hz, 2H), 8.24 (d, J=7.5 Hz, 1H), 8.20 (s, 1H), 7.95 (s, 1H), 7.85 (s,1H), 7.71 (s, 1H), 7.39 (d, J=9.4 Hz, 1H), 6.99 (d, J=9.3 Hz, 1H), 6.72(dd, J=7.4, 1.8 Hz, 1H), 5.38 (s, 2H), 4.54 (d, J=5.7 Hz, 2H), 1.98-1.87(m, 1H), 1.01-0.76 (m, 2H), 0.76-0.55 (m, 2H).

Example 6

Synthesis of tert-butyl ((mesitylsulfonyl)oxy)carbamate

To a mixture of tert-butyl hydroxycarbamate (3 g, 22.5 mmol) and2,4,6-trimethylbenzenesulfonyl chloride (4.9 g, 22.5 mmol) in MTBE (100mL) was added Et₃N (2.43 g, 24.0 mmol) at 0° C. The mixture was stirredat 0° C. for 2 h. The reaction mixture was filtered and washed withMTBE. The filtrate was concentrated to give tert-butyl((mesitylsulfonyl)oxy)carbamate (7.1 g, yield: 100%) as a light yellowsolid. ESI-MS [M+Na]⁺: 338.1.

Synthesis of O-(mesitylsulfonyl)hydroxylamine

The mixture of tert-butyl ((mesitylsulfonyl)oxy)carbamate (5.9 g, 18.71mmol) in TFA (20 mL) was stirred for at 0° C. for 2 h. The reactionmixture was poured into H₂O (150 mL) and stirred for 30 min. Theprecipitate was collected and dried to giveO-(mesitylsulfonyl)hydroxylamine (2.2 g, yield: 55%) as a white solidwhich was used into next step without further purification. ESI-MS[M+H]⁺: 216.2.

Synthesis of 5-cyclopropylpyridin-2-amine

The mixture of 5-bromopyridin-2-amine (4 g, 23.12 mmol),cyclopropylboronic acid (2.98 g, 34.68 mmol), Pd(OAc)₂ (130 mg, 0.578mmol), tricyclohexyl phosphine (324 mg, 1.16 mmol) and K₃PO₄ (17.18 g,80.92 mmol) in toluene (100 mL) and H₂O (10 mL) was stirred at 90° C.for 16 h. The reaction mixture was filtered and rinsed with EtOAc. Thecombined filtrate was washed with H₂O (150 mL×1) and brine (150 mL×1),dried over Na₂SO₄, concentrated and purified by silica gelchromatography (EA/PE=1/1) to give 5-cyclopropylpyridin-2-amine (2.76 g,yield: 89%) as a yellow solid. ESI-MS [M+H]⁺: 135.2.

Synthesis of 5-cyclopropyl-2-iminopyridin-1(2H)-amine2,4,6-trimethylbenzenesulfonate

To a stirred solution of O-(mesitylsulfonyl)hydroxylamine (2.2 g, 10.22mmol) in DCM (40 mL) was added 5-cyclopropylpyridin-2-amine (1.37 g,10.22 mmol) in four portions at 0° C. The mixture was stirred at 0° C.for 10 min and warmed to RT and stirred for 1 h. The reaction mixturewas concentrated and dried in vacuo to give5-cyclopropyl-2-iminopyridin-1(2H)-amine 2,4,6-trimethylbenzenesulfonate(3.57 g, yield: 100%) as a light brown syrup. ESI-MS [M+H]⁺: 150.2.

Synthesis of Ethyl6-cyclopropyl-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylate

To a stirred solution of 5-cyclopropyl-2-iminopyridin-1(2H)-amine2,4,6-trimethylbenzenesulfonate (3.57 g, 10.22 mmol) in pyridine (30 mL)was added ethyl 2-chloro-2-oxoacetate (2.79 g, 20.44 mmol) at RT. Themixture was stirred at 100° C. for 16 h. The reaction mixture wasconcentrated. The residue was dissolved in EtOAc (100 mL) and washedwith H₂O (100 mL×1) brine (100 mL×1), dried over Na₂SO₄, concentratedand purified by silica gel chromatography (EA/PE=1/1) to give ethyl6-cyclopropyl-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylate (1.1 g,yield: 47%) as a yellow solid. ESI-MS [M+H]⁺: 232.1.

Synthesis of (6-cyclopropyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)methanol

To a stirred solution of ethyl6-cyclopropyl-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylate (300 mg, 1.30mmol) in MeOH (10 mL) was added NaBH₄ (246 mg, 6.5 mmol) in portions at0° C. The mixture was stirred at RT for 2 h. The reaction mixture wasthen quenched with NH₄C aqueous. MeOH was removed and the reaction wasdiluted with H₂O (50 mL) and extracted with EtOAc (30 mL×3). Thecombined organics was washed with brine (80 mL×1), dried over Na₂SO₄,concentrated and purified by silica gel chromatography (EA/MeOH=10/1) togive (6-cyclopropyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)methanol (210 mg,yield: 85%) as a yellow solid. ESI-MS [M+H]⁺: 190.2.

Synthesis of2-(chloromethyl)-6-cyclopropyl-[1,2,4]triazolo[1,5-a]pyridine

To a stirred solution of(6-cyclopropyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)methanol (110 mg, 0.58mmol) in DCM (5 mL) was added SOCl₂ (690 mg, 5.8 mmol) at 0° C. Themixture was stirred at RT for 1 h. The reaction mixture was thenconcentrated, the residue was dissolved in EtOAc (60 mL) and washed withNaHCO₃ (50 mL×1), brine (50 mL×1), dried over Na₂SO₄, concentrated togive 2-(chloromethyl)-6-cyclopropyl-[1,2,4]triazolo[1,5-a]pyridine (115mg, yield: 96%) as a yellow solid, which was used into next step withoutfurther purification. ESI-MS [M+H]⁺: 208.1.

Synthesis ofN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(I-6)

The mixture of2-(chloromethyl)-6-cyclopropyl-[1,2,4]triazolo[1,5-a]pyridine (15.8 mg,0.0762 mmol),N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide(20 mg, 0.0725 mmol) and Cs₂CO₃ (35 mg, 0.109 mmol) in DMF (3 mL) wasstirred at RT for 2 h. The reaction mixture was poured into H₂O (30 mL)and extracted with EtOAc (50 mL×3). The combined organic layers werewashed with brine (60 mL×3), dried over Na₂SO₄, concentrated andpurified by prep-TLC (DCM/MeOH=5/1) to giveN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(15 mg, yield: 47%) as a yellow solid. ESI-MS [M+H]⁺: 447.1. Purity:99%. ¹H NMR (400 MHz, DMSO): δ 8.73 (s, 1H), 8.62 (t, J=5.7 Hz, 1H),8.31 (d, J=7.9 Hz, 3H), 7.86 (s, 1H), 7.80 (d, J=0.9 Hz, 1H), 7.66 (d,J=9.2 Hz, 1H), 7.42 (dd, J=9.2, 1.7 Hz, 1H), 6.65 (dd, J=7.5, 2.1 Hz,1H), 5.56 (s, 2H), 4.57 (d, J=5.7 Hz, 2H), 2.03 (m, 1H), 0.97 (m, 2H),0.78 (m, 2H).

Example 7

Synthesis of 6-chloro-2-(chloromethyl)-5-methylimidazo[1,2-a]pyridine

To a solution (6-chloro-5-methylimidazo[1,2-a]pyridin-2-yl)methanol (60mg, 0.31 mmol) in DCM (10 mL) was added SOCl₂ (1 mL) at RT. Theresulting reaction was stirred at 45° C. for 2 h. The solution wasevaporated to give the6-chloro-2-(chloromethyl)-5-methylimidazo[1,2-a]pyridine (50 mg, crude)as a light yellow solid, which was used in the next step without furtherpurification. ESI-MS [M+H]⁺: 215.2.

Synthesis of1-((6-chloro-5-methylimidazo[1,2-a]pyridin-2-yl)methyl)-N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide(I-7)

To a solution 6-chloro-2-(chloromethyl)-5-methylimidazo [1,2-a]pyridine(50 mg, 0.23 mmol) in DMF (10 mL) was addedN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide(41 mg, 0.15 mmol) and Cs₂CO₃ (146 mg, 0.45 mmol) at RT. The resultingreaction was stirred at RT for 12 h. H₂O (30 mL) was added to thereaction and then extracted with EtOAc (20 mL×3). The combined organiclayers were washed with brine, dried over Na₂SO₄, concentrated in vacuoto give the crude, which was purified with prep-TLC (DCM/MeOH=10/1) togive1-((6-chloro-5-methylimidazo[1,2-a]pyridin-2-yl)methyl)-N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide(40 mg, yield: 58%) as a white solid. ESI-MS [M+H]⁺: 454.1. Purity:100%. ¹H NMR (400 MHz, DMSO): δ 8.59 (t, J=5.5 Hz, 1H), 8.31-8.29 (m,2H), 8.23 (s, 1H), 7.92 (s, 1H), 7.86 (s, 1H), 7.78 (s, 1H), 7.47 (d,J=9.5 Hz, 1H), 7.34 (d, J=9.5 Hz, 1H), 6.65 (d, J=7.4 Hz, 1H), 5.44 (s,2H), 4.55 (d, J=5.6 Hz, 2H), 2.66 (s, 3H).

Example 8

Synthesis of (7-isopropylimidazo[1,2-a]pyridin-2-yl)methanol

To a solution of ethyl 7-isopropylimidazo[1,2-a]pyridine-2-carboxylate(200 mg, 0.86 mmol) in THF (4 mL) was added LiAlH4 (65.5 mg, 1.72 mmol).The resulting reaction was stirred at RT for 4 h. The reaction wasquenched with saturated Na₂SO₄ (aq.), filtered and concentrated andpurified by silica gel column (DCM/MeOH=10/1) to give the(7-isopropylimidazo[1,2-a]pyridin-2-yl)methanol (130 mg, 80%) as a brownliquid. ESI-MS [M+H]⁺: 191.2.

Synthesis of 2-(chloromethyl)-7-isopropylimidazo[1,2-a]pyridine

To a solution of (7-isopropylimidazo[1,2-a]pyridin-2-yl)methanol (190mg, 1 mmol) in DCM (10 mL) was added SOCl₂ (2 mL). The resultingreaction was stirred at 50° C. for 2 h. The reaction was concentrate invacuo to give 2-(chloromethyl)-7-isopropylimidazo[1,2-a]pyridine (220 mgcrude), which was used into next step without further purification.ESI-MS [M+H]⁺: 209.2.

Synthesis ofN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-isopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(I-8)

A mixture of 2-(chloromethyl)-7-isopropylimidazo[1,2-a]pyridine (46 mg,0.22 mmol),N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide(38 mg, 0.14 mmol) and Cs₂CO₃ (142 mg, 0.44 mmol) in DMF (8 mL) wasstirred at 80° C. for 12 h. H₂O (15 mL) was added to the reaction,extracted with EtOAc (20 mL×3). The combined organic layers were washedwith brine, dried over Na₂SO₄, concentrated in vacuo to give the crude,which was purified with prep-TLC (DCM/MeOH=10/1) to give theN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-isopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(15 mg, 24%) as a white solid. ESI-MS [M+H]⁺: 448.2. Purity: 100%. ¹HNMR (400 MHz, DMSO): δ 8.58 (t, J=5.6 Hz, 1H), 8.32 (m, 3H), 8.20 (s,1H), 7.85 (s, 1H), 7.77 (m, 2H), 7.43 (d, J=9.3 Hz, 1H), 7.21 (d, J=9.3Hz, 1H), 6.64 (dd, J=7.4, 1.9 Hz, 1H), 5.39 (s, 2H), 4.55 (d, J=5.7 Hz,2H), 2.96-2.80 (m, 1H), 1.22 (d, J=6.9 Hz, 6H).

Example 9

Synthesis of (5-methylimidazo[1,2-a]pyridin-2-yl)methanol

A solution of 5-chloro-6-methylpyridin-2-amine (568 mg, 4.0 mmol), ethyl3-bromo-2-oxopropanoate (1.2 g, 6.0 mmol) in dry EtOH (10 mL) wasstirred at 80° C. for 8 h. The mixture was concentrated and purified bysilica gel chromatography (DCM/MeOH=20/1) to give ethyl6-chloro-5-methylimidazo[1,2-a]pyridine-2-carboxylate (800 mg, yield:84.0%) as a yellow solid. ESI-MS [M+H]⁺: 239.1.

Synthesis of (5-methylimidazo[1,2-a]pyridin-2-yl)methanol

To a solution of ethyl6-chloro-5-methylimidazo[1,2-a]pyridine-2-carboxylate (240 mg, 1.0 mmol)in dry THF (10 mL) was added LiAlH₄ (115 mg, 3.0 mmol) slowly at 0° C.The reaction mixture was stirred at RT for 5 h, then quenched withNa₂SO₄.10H₂O. The mixture was filtered and the filtrate was washed withEtOAc (20 mL). The filtrate was concentrated to give(5-methylimidazo[1,2-a]pyridin-2-yl)methanol (150 mg, yield: 92%) as ayellow oil which was used in the next step without further purification.ESI-MS [M+H]⁺: 163.1.

Synthesis of 2-(chloromethyl)-5-methylimidazo[1,2-a]pyridine

To a solution of (5-methylimidazo[1,2-a]pyridin-2-yl)methanol (150 mg,0.925 mmol) in dry DCM (5 mL) was added SOCl₂ (0.5 mL) at RT. Themixture was stirred at 40° C. for 1 h. The mixture was concentrated togive crude 2-(chloromethyl)-5-methylimidazo[1,2-a]pyridine (140 mg,yield: 94.6%) as a yellow solid. ESI-MS [M+H]⁺: 181.2.

Synthesis ofN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((5-methylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(I-9)

A mixture of 2-(chloromethyl)-5-methylimidazo[1,2-a]pyridine (30 mg,0.16 mmol),N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide(30 mg, 0.11 mmol) and Cs₂CO₃ (110 mg, 0.33 mmol) in DMF (3 mL) wasstirred at RT for 16 h. Water (30 mL) was added and the reaction wasextracted with EtOAc (30 mL×3). The combined organic layers wereconcentrated and purified by prep-TLC (DCM/MeOH=10/1) to giveN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((5-methylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(11.5 mg, yield: 25%) as a light yellow solid. ESI-MS [M+H]⁺: 420.1.Purity: 97.4%. ¹H NMR (400 MHz, DMSO): δ 8.58 (t, J=5.4 Hz, 1H),8.31-8.29 (m, 2H), 8.23 (s, 1H), 7.86 (s, 1H), 7.78 (s, 2H), 7.41 (d,J=9.1 Hz, 1H), 7.24-7.20 (m, 1H), 6.78 (d, J=6.8 Hz, 1H), 6.64 (dd,J=7.5, 1.9 Hz, 1H), 5.43 (s, 2H), 4.55 (d, J=5.7 Hz, 2H), 2.56 (s, 3H).

Example 10

Synthesis of Ethyl1-((6-(prop-1-en-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate

A mixture of ethyl1-((6-chloroimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate(600 mg, 1.97 mmol),4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (662 mg, 3.94mmol), Pd(dppf)₂C12 (160 mg, 0.2 mmol) and K₃PO₄ (1.25 g, 5.91 mmol) indioxane/H₂O (20 mL/2 mL) was stirred at 115° C. for 24 h. H₂O (50 mL)was added to the reaction, extracted with EtOAc (50 mL×3). The combinedorganic layers were washed with brine, dried over Na₂SO₄, andconcentrated in vacuo to give the crude, which was purified by prep-HPLC(chromatographic columns: Gemini-C18 150×21.2 mm, 5 um, mobile phase:acetonitrile-H₂O (0.1% FA), gradient: 10-20) to give ethyl1-((6-(prop-1-en-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate(450 mg, yield: 73%) as a white solid. ESI-MS [M+H]⁺: 311.2.

Synthesis of Ethyl1-((6-(1-methylcyclopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate

To a solution of Zn(Et)₂ (1.9 mL, 1 M solution in hexane, 1.9 mmol) inDCM (4 mL) was added TFA (220 mg, 1.9 mmol, in 1 mL DCM) dropwisely at0° C. The resulting reaction was stirred at 0° C. for 20 min. Then asolution of CH₂I₂ (509 mg, 1.9 mmol, in 2 mL DCM) was added at 0° C.After stirring for another 20 min, a solution of ethyl1-((6-(prop-1-en-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate(50 mg, 0.16 mmol) in DCM (1 mL) was added. The resulting reaction waswarmed to RT and stirred for 16 h. The reaction was quenched with H₂O(20 mL) and extracted with DCM (25 mL×3). The combined organic layerswere washed with brine, dried over Na₂SO₄, and concentrated in vacuo togive the crude, which was purified with prep-TLC (DCM/MeOH=15/1) to giveethyl1-((6-(1-methylcyclopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate(17 mg, yield: 33%) as a yellow solid. ESI-MS [M+H]⁺: 325.1.

Synthesis of1-((6-(1-methylcyclopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylicAcid

A mixture of ethyl1-((6-(1-methylcyclopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate(17 mg, 0.052 mmol) and LiOH (4 mg, 0.16 mmol) in THF/MeOH/H₂O (2 mL/2mL/1 mL) was stirred at 70° C. for 2 h. The pH of the reaction wasadjusted to 4 and H₂O (5 mL) was added and the mixture was extractedwith EtOAc (20 mL×3). The combined organic layers were then concentratedin vacuo to give the1-((6-(1-methylcyclopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylicacid (15 mg, yield: 98%) as a yellow oil which was used in the next stepwithout further purification. ESI-MS [M+H]⁺: 297.1.

Synthesis ofN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-(1-methylcyclopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(I-10)

To a solution of1-((6-(1-methylcyclopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylicacid (15 mg, 0.05 mmol), (7-chloroimidazo[1,5-a]pyridin-1-yl)methanaminehydrochloride (13 g, 0.06 mmol) and HATU (28 mg, 0.075 mmol) in DMF (3mL) was added DIPEA (32 mg, 0.25 mmol). The resulting reaction wasstirred at RT for 12 h. H₂O (15 mL) was added to the reaction and thenextracted with EtOAc (25 mL×3). The combined organic layers were washedwith brine, dried over Na₂SO₄, concentered in vacuo to give the crude,which was purified with prep-TLC (DCM/MeOH=10/1) to giveN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-(1-methylcyclopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(7.5 mg, yield: 33%) as a white solid. ESI-MS [M+H]⁺: 460.2. Purity:93.5%. ¹H NMR (400 MHz, MeOD): δ 8.27-8.25 (m, 2H), 8.16 (d, J=7.5 Hz,1H), 8.12 (s, 1H), 7.91 (s, 1H), 7.73-7.72 (m, 2H), 7.40 (d, J=9.4 Hz,1H), 7.26 (d, J=9.4 Hz, 1H), 6.62 (d, J=7.3 Hz, 1H), 5.44 (s, 2H), 4.68(s, 2H), 1.41 (s, 3H), 0.90-0.87 (m, 2H), 0.78-0.76 (m, 2H).

Synthesis of 6-chloro-2-(chloromethyl)imidazo[1,2-b]pyridazine

A solution of 6-chloropyridazin-3-amine (5 g, 39 mmol) and 1,3-dichloropropan-2-one (20 g, 156 mmol) in EtOH (50 mL) was stirred at90° C. for 4 h. Then the reaction mixture was diluted with H₂O (100 mL)and extracted with EtOAc (100 mL×3). The combined organic layers weredried over Na₂SO₄, concentrated and purified by column chromatography(PE/EA=5/1) to give the desired product6-chloro-2-(chloromethyl)imidazo[1,2-b]pyridazine (2.6 g, yield: 33%) asa yellow solid. ESI-MS [M+H]⁺: 202.2.

Synthesis ofN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methyl)-1H-pyrazole-4-carboxamide(I-11)

A solution of 6-chloro-2-(chloromethyl)imidazo[1,2-b]pyridazine (50 mg,0.25 mmol),N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide(66 mg, 0.24 mmol), Cs₂CO₃ (160 mg, 0.5 mmol) in DMF (3 mL) was stirredat RT for 2 h. Then the reaction mixture was diluted with H₂O (30 mL)and extracted with EtOAc (30 mL×3). The combined organic layers weredried over Na₂SO₄, concentrated and purified by column chromatography(CH₂Cl₂/MeOH=10/1) to give the desired compoundN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methyl)-1H-pyrazole-4-carboxamide(29.5 mg, yield: 27%) as a white solid. ESI-MS [M+H]⁺: 441.1. Purity:98%. ¹H NMR (400 MHz, DMSO): δ 8.58 (s, 1H), 8.31 (s, 3H), 8.25 (s, 1H),8.17 (d, J=9.3 Hz, 1H), 7.86 (s, 1H), 7.78 (s, 1H), 7.38 (d, J=9.5 Hz,1H), 6.65 (d, J=7.1 Hz, 1H), 5.47 (s, 2H), 4.56 (d, J=5.0 Hz, 2H).

Example 12

Synthesis of 2-(chloromethyl)-7-cyclopropylimidazo[1,2-a]pyridine

To a solution of (7-cyclopropylimidazo[1,2-a]pyridin-2-yl)methanol (126mg, 0.67 mmol) in DCM (10 mL) was added SOCl₂ (2 mL). The resultingreaction was stirred at 45° C. for 4 h. The reaction was concentrated invacuo to give the 2-(chloromethyl)-7-cyclopropylimidazo[1,2-a]pyridine(150 mg crude), which was used in the next step without furtherpurification. ESI-MS [M+H]⁺: 207.2.

Synthesis of Ethyl1-((7-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate

A mixture of 2-(chloromethyl)-7-cyclopropylimidazo[1,2-a]pyridine (0.15g crude from previous step), ethyl 1H-pyrazole-4-carboxylate (126 mg,0.9 mmol) and Cs₂CO₃ (1.17 g, 3.6 mmol) in DMF (8 mL) was stirred at 80°C. for 12 h. H₂O (15 mL) was added to the reaction and then extractedwith EtOAc (20 mL×3). The combined organic layers were washed withbrine, dried over Na₂SO₄, concentrated in vacuo to give the crude, whichwas purified with prep-TLC (DCM/MeOH=10/1) to give ethyl1-((7-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate(100 mg, 36%) as a yellow solid. ESI-MS [M+H]⁺: 311.2.

Synthesis of1-((7-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylicAcid

A mixture of ethyl1-((7-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate(600 mg, 1.94 mmol) and LiOH (270 mg, 11.6 mmol) in THF/EtOH/H₂O (6 mL/6mL/4 mL) was stirred at 80° C. for 2 h. The pH of reaction was adjustedto around 5 and a yellow solid was precipitated out. The mixture wasfiltered and the solid was dried to give1-((7-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylicacid (550 mg, yield: 100%) as a brown solid. ESI-MS [M+H]⁺: 283.1.

Synthesis of1-((7-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-((6-methoxyimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(I-12)

To a solution of1-((7-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylicacid (23 mg, 0.08 mmol),(7-methoxyimidazo[1,5-a]pyridin-1-yl)methanamine (14 mg, 0.08 mmol) andHATU (45.6 mg, 0.12 mmol) in DMF (3 mL) was added DIPEA (30 mg, 0.24mmol). The resulting reaction stirred at RT for overnight. H₂O (20 mL)was added to the reaction and then extracted with EtOAc (30 mL×3). Thecombined organic layers were washed with brine, dried over Na₂SO₄, andconcentrated in vacuo to give the crude, which was purified withprep-TLC (DCM/MeOH=10/1) to give1-((7-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-((6-methoxyimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(30 mg, yield: 85%). ESI-MS [M+H]⁺: 442.1. Purity: 98.3%. ¹H NMR (400MHz, MeOD): δ 8.22 (s, 1H), 8.15 (s, 1H), 8.12 (s, 1H), 8.06 (d, J=7.6Hz, 1H), 7.94 (s, 1H), 7.73 (s, 1H), 7.41 (d, J=9.4 Hz, 1H), 7.14 (d,J=9.4 Hz, 1H), 6.90 (s, 1H), 6.41 (dd, J=7.6, 2.2 Hz, 1H), 5.46 (s, 2H),4.69 (s, 2H), 3.81 (s, 3H), 2.05-1.83 (m, 1H), 1.07-0.92 (m, 2H),0.86-0.63 (m, 2H).

Example 13

Synthesis of Ethyl6-cyclopropyl-5-methylimidazo[1,2-a]pyridine-2-carboxylate

A mixture of 5-cyclopropyl-6-methylpyridin-2-amine (1.3 g, 8.78 mmol),ethyl 3-bromo-2-oxopropanoate (3.5 g, 17.57 mmol) in EtOH (30 mL) wasstirred at 90° C. for 16 h. The mixture was concentrated and purified bysilica gel chromatography (DCM/MeOH=20/1) to give ethyl6-cyclopropyl-5-methylimidazo[1,2-a]pyridine-2-carboxylate (150 mg,yield: 7%) as a yellow solid. ESI-MS [M+H]⁺: 245.1.

Synthesis of (6-cyclopropyl-5-methylimidazo[1,2-a]pyridin-2-yl)methanol

To a solution of ethyl6-cyclopropyl-5-methylimidazo[1,2-a]pyridine-2-carboxylate (110 mg, 0.45mmol) in dry THF (5 mL) was added LiAlH₄ (50 mg, 1.12 mmol) slowly at 0°C. After the mixture was stirred at RT for 1 h, it was quenched withNa₂SO₄.10H₂O. The mixture was filtered and the filtrate was washed withEtOAc (20 mL). The filtrate was concentrated and purified by prep-TLC(DCM/MeOH=15/1) to give(6-cyclopropyl-5-methylimidazo[1,2-a]pyridin-2-yl) methanol (50 mg,yield: 55%) as a yellow solid. ESI-MS [M+H]⁺: 203.1.

Synthesis of2-(chloromethyl)-6-cyclopropyl-5-methylimidazo[1,2-a]pyridine

To a solution of(6-cyclopropyl-5-methylimidazo[1,2-a]pyridin-2-yl)methanol (50 mg, 0.25mmol) in dry DCM (2.5 mL) was added SOCl₂ (0.5 mL) at RT. The mixturewas stirred at 40° C. for 1 h. The mixture was concentrated to give2-(chloromethyl)-6-cyclopropyl-5-methylimidazo [1,2-a]pyridine (50 mg,yield: 90.9%) as a yellow oil. which was used in the next step withoutfurther purification. ESI-MS [M+H]⁺: 221.2.

Synthesis ofN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-5-methylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(I-13)

A mixture of2-(chloromethyl)-6-cyclopropyl-5-methylimidazo[1,2-a]pyridine (25 mg,0.11 mmol),N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide(30 mg, 0.11 mmol) and Cs₂CO₃ (110 mg, 0.33 mmol) in DMF (3 mL) wasstirred at 50° C. for 2 h. Water (20 mL) was added and extracted withEtOAc (20 mL×3). The combined organic layers were concentrated andpurified by prep-TLC (DCM/MeOH=10/1) to giveN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-5-methylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(17 mg, yield: 33.7%) as a light yellow solid. ESI-MS [M+H]⁺: 460.2.Purity: 99.5%. ¹H NMR (400 MHz, DMSO): δ 8.57 (s, 1H), 8.30 (d, J=7.1Hz, 2H), 8.20 (s, 1H), 7.85 (s, 1H), 7.77 (s, 2H), 7.33 (d, J=9.6 Hz,1H), 6.97 (d, J=8.6 Hz, 1H), 6.64 (d, J=7.3 Hz, 1H), 5.40 (s, 2H), 4.54(d, J=5.1 Hz, 2H), 2.64 (s, 3H), 2.02 (s, 1H), 0.94 (d, J=8.2 Hz, 2H),0.64 (s, 2H).

Example 14

Synthesis of Ethyl1-((6-cyclopropyl-5-methylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate

A mixture of2-(chloromethyl)-6-cyclopropyl-5-methylimidazo[1,2-a]pyridine (65 mg,0.30 mmol), ethyl 1H-pyrazole-4-carboxylate (45 mg, 0.32 mmol) andCs₂CO₃ (245 mg, 0.75 mmol) in DMF (5 mL) was stirred at 50° C. for 2 h.Water (20 mL) was added and extracted with EtOAc (20 mL×3). The combinedorganic layers were concentrated to give ethyl1-((6-cyclopropyl-5-methylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate(65 mg, yield: 67%) as a yellow solid. ESI-MS [M+H]⁺: 325.1.

Synthesis of1-((6-cyclopropyl-5-methylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylicAcid

A solution of ethyl1-((6-cyclopropyl-5-methylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate(65 mg, 0.2 mmol) and LiOH.H₂O (25 mg, 0.6 mmol) in THF/MeOH/H₂O (1 mL/1mL/0.5 mL) was stirred at 80° C. for 1 h. The pH of the mixture wasadjusted to 4 by adding 1 M HCl solution. Water (10 mL) was added andthe reaction was extracted with EtOAc (20 mL×3). The combined organiclayers were concentrated to give1-((6-cyclopropyl-5-methylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylicacid (59 mg, yield: 99.7%) as a yellow oil. which was used directly inthe next step without further purification. ESI-MS [M+H]⁺: 297.1.

Synthesis ofN-((7-bromoimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-5-methylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(I-14)

A mixture of1-((6-cyclopropyl-5-methylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylicacid (59 mg, 0.2 mmol), (7-bromoimidazo[1,5-a]pyridin-1-yl)methanamine(70 mg, 0.25 mmol), HATU (120 mg, 0.3 mmol) and DIPEA (0.1 mL, 0.6 mmol)in DMF (4 mL) was stirred at RT for 2 h. Water (20 mL) was added and thereaction was extracted with EtOAc (30 mL×3). The organic layers wereconcentrated and purified by prep-TLC (DCM/MeOH=10/1) to giveN-((7-bromoimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-5-methylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(42.2 mg, yield: 41.9%) as a white solid. ESI-MS [M+H]⁺: 504.1. Purity:93.5%. ¹H NMR (400 MHz, DMSO): δ 8.57 (t, J=5.7 Hz, 1H), 8.31 (s, 1H),8.27-8.17 (m, 2H), 7.94 (s, 1H), 7.85 (s, 1H), 7.77 (s, 1H), 7.33 (d,J=9.3 Hz, 1H), 6.97 (d, J=9.3 Hz, 1H), 6.71 (dd, J=7.4, 1.9 Hz, 1H),5.41 (s, 2H), 4.54 (d, J=5.7 Hz, 2H), 2.64 (s, 3H), 2.01-1.98 (m, 1H),0.94 (dd, J=8.4, 1.7 Hz, 2H), 0.74-0.58 (m, 2H).

Example 15

Synthesis of 6-chloro-2-(chloromethyl)imidazo[1,2-b]pyridazine

A solution of 6-chloropyridazin-3-amine (20.0 g, 155.0 mmol) and1,3-dichloropropan-2-one (49.2 g, 387.5 mmol) in EtOH (200 mL) wasstirred at 80° C. for 4 h. Then the reaction mixture was concentratedand diluted with H₂O (300 mL×3) and extracted with EtOAc (500 mL×3). Thecombined organic layer were dried over Na₂SO₄, concentrated and purifiedby column chromatography (DCM:MeOH=10:1) to give the desired product6-chloro-2-(chloromethyl)imidazo[1,2-b]pyridazine (17.0 g, yield: 54%)as a yellow solid. ESI-MS [M+H]⁺: 202.1.

Synthesis of Ethyl1-((6-chloroimidazo[1,2-b]pyridazin-2-yl)methyl)-1H-pyrazole-4-carboxylate

A solution of 6-chloro-2-(chloromethyl)imidazo[1,2-b]pyridazine (10.0 g,49.5 mmol), ethyl 1H-pyrazole-4-carboxylate (6.2 g, 44.5 mmol), Cs₂CO₃(48.4 g, 148.5 mmol) in DMF (200 mL) was stirred at RT for 2 h. Most ofthe DMF was concentrated, the residue was diluted with H₂O (300 mL) andextracted with EtOAc (500 mL×3). The combined organic layer were driedover Na₂SO₄, concentrated and purified by column chromatography(EtOAc:PE=2:1) to give the desired compound ethyl1-((6-chloroimidazo[1,2-b]pyridazin-2-yl)methyl)-1H-pyrazole-4-carboxylate(10.0 g, yield: 65%) as a yellow solid, ESI-MS [M+H]⁺: 306.1.

Synthesis of Methyl1-((6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methyl)-1H-pyrazole-4-carboxylate

A solution of ethyl1-((6-chloroimidazo[1,2-b]pyridazin-2-yl)methyl)-1H-pyrazole-4-carboxylate(10.0 g, 32 mmol), cyclopropylboronic acid (4.2 g, 49 mmol), Pd(OAc)₂(718.4 mg, 3.2 mmol), SPhos (1.3 g, 3.2 mmol) and K₃PO₄ (21.0 g, 96mmol) in Tol/H₂O (100 mL/10 mL) was stirred at RT for 2 h. Then thereaction mixture was diluted with H₂O (100 mL) and extracted with EtOAc(300 mL×3). The combined organic layer were dried over Na₂SO₄,concentrated and purified by column chromatography (EtOAc:PE=2:1) togive the desired compound ethyl1-((6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methyl)-1H-pyrazole-4-carboxylate(9.8 g, yield: 100%) as a white solid. ESI-MS [M+H]⁺: 312.2.

Synthesis of1-((6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methyl)-1H-pyrazole-4-carboxylicAcid

A solution of ethyl1-((6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methyl)-1H-pyrazole-4-carboxylate(9.8 g, 32.0 mmol) and LiOH (1.5 g, 64.0 mmol) in THF/EtOH/H₂O (80 mL/80mL/80 mL) was stirred at 80° C. for 2 h. Then the reaction mixture wasconcentrated and diluted with H₂O (50 mL). The pH of the solution wasadjusted to 5 by adding 1 M HCl solution. Solid precipitated and wasfiltered to give the desired compound1-((6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methyl)-1H-pyrazole-4-carboxylicacid (9.5 g, yield: 104.6%) as a white solid. ESI-MS [M+H]⁺: 284.1.

Synthesis ofN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methyl)-1H-pyrazole-4-carboxamide(I-15)

A solution of1-((6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methyl)-1H-pyrazole-4-carboxylicacid (9.5 g, 33.5 mmol), (7-chloroimidazo[1,5-a]pyridin-1-yl)methanamine(9.5 g, 43.5 mmol), EDCI (7.7 g, 40.2 mmol), HOBT (5.4 g, 40.2 mmol) andTEA (10.1 g, 13.9 mL, 100.5 mmol) in dry DCM (800 mL) was stirred at RTovernight. Then the reaction mixture was diluted with H₂O (500 mL×3) andextracted with DCM (1 L×3). The combined organic layer were dried overNa₂SO₄, concentrated and purified by column chromatography(DCM:MeOH=10:1) to give the desired compoundN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methyl)-1H-pyrazole-4-carboxamide(6.1 g, yield: 40.9%) as a white solid. ESI-MS [M+H]⁺: 447.1. Purity:99.05%. ¹H NMR (400 MHz, DMSO): δ 8.58-8.55 (t, J=5.7 Hz, 1H), 8.30-8.28(m, J=7.5, 0.6 Hz, 2H), 8.21 (s, 1H), 8.07 (s, 1H), 7.91 (d, J=9.5 Hz,1H), 7.84 (s, 1H), 7.77-7.76 (m, 1H), 7.08 (d, J=9.5 Hz, 1H), 6.63 (dd,J=7.5, 2.1 Hz, 1H), 5.40 (s, 2H), 4.54 (d, J=5.7 Hz, 2H), 2.50-2.14 (m,J=9.0, 4.1 Hz, 1H), 1.07-1.03 (m, J=6.0, 4.1 Hz, 2H), 0.97-0.93 (m, 2H).

Example 16

Synthesis of 5-cyclopropyl-4-methylpyridin-2-amine

To a solution of 5-bromo-4-methylpyridin-2-amine (2 g, 10.7 mmol) intoluene/H₂O (50 mL/5 mL) was added cyclopropylboronic acid (1.36 g, 16.0mmol), Pd(OAc)₂ (240 mg, 1.07 mmol), SPhos (439 mg, 1.07 mmol) and K₃PO₄(6.8 g, 32.1 mmol). The reaction mixture was stirred at 95° C. for 12 hunder nitrogen, then diluted with DCM (200 mL), washed with H₂O andbrine, and concentrated to give the crude residue which was purified bysilica gel chromatography (PE/EtOAc=1/1) to afford5-cyclopropyl-4-methylpyridin-2-amine as a yellow solid (4 g, yield:90%). ESI-MS [M+H]⁺: 149.2.

Synthesis of2-(chloromethyl)-6-cyclopropyl-7-methylimidazo[1,2-a]pyridine

To a solution 5-cyclopropyl-4-methylpyridin-2-amine (200 mg, 1.35 mmol)in DMF (10 mL) was added 1,3-dichloropropan-2-one (514 mg, 4.05 mmol) atRT. The resulting reaction was stirred at 85° C. for 2 h. The solutionwas quenched with H₂O (30 mL), adjusted to pH 8 by adding saturatedNaHCO₃ solution, and then extracted with EtOAc (30 mL×3). The combinedorganic layers were washed with brine, dried over Na₂SO₄, andconcentrated in vacuo to give the crude, which was purified by prep-TLC(PE/EtOAc=1/1) to give the2-(chloromethyl)-6-cyclopropyl-7-methylimidazo[1,2-a]pyridine (150 mg,yield: 51%) as a light yellow oil. ESI-MS [M+H]⁺: 221.2.

Synthesis ofN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-7-methylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(I-17)

To a solution2-(chloromethyl)-6-cyclopropyl-7-methylimidazo[1,2-a]pyridine (55 mg,0.25 mmol) in DMF (4 mL) was addedN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide(45 mg, 0.16 mmol) and Cs₂CO₃ (156 mg, 0.48 mmol) at RT. The resultingreaction was stirred at RT for 12 h. H₂O (20 mL) was added to thereaction and extracted with EtOAc (30 mL×3). The combined organic layerswere washed with brine, dried over Na₂SO₄, concentrated in vacuo to givethe crude, which was purified by prep-TLC (DCM/MeOH=10/1) to give theN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-7-methylimidazo[1,2-a]pyridine-2-yl)methyl)-1H-pyrazole-4-carboxamide(20 mg, yield: 27%) as a white solid. ESI-MS [M+H]⁺: 460.1. ¹H NMR (400MHz, DMSO): δ 8.58 (t, J=5.7 Hz, 1H), 8.35-8.27 (m, 2H), 8.23 (s, 1H),8.19 (s, 1H), 7.86 (s, 1H), 7.79-7.74 (m, 1H), 7.66 (s, 1H), 7.30 (s,1H), 6.66-6.63 (m, 1H), 5.38 (s, 2H), 4.55 (d, J=5.7 Hz, 2H), 2.42 (s,3H), 1.88-1.82 (m, 1H), 0.94-0.84 (m, 2H), 0.62-0.54 (m, 2H).

Example 17

Synthesis ofN-((7-bromoimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-7-methylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(I-17)

To a solution of2-(chloromethyl)-6-cyclopropyl-7-methylimidazo[1,2-a]pyridine (50 mg,0.23 mmol) in DMF (4 mL) was addedN-((7-bromoimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide(48 mg, 0.15 mmol) and Cs₂CO₃ (147 mg, 0.45 mmol) at RT. The resultingreaction was stirred at RT for 12 h. the reaction was quenched with H₂O(20 mL) and extracted with EtOAc (30 mL×3). The combined organic layerswere washed with brine, dried over Na₂SO₄, concentrated in vacuo to givethe crude, which was purified by prep-TLC (DCM/MeOH=10/1) to give theN-((7-bromoimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-7-methylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(22 mg, yield: 29%) as a white solid. ESI-MS [M+H]⁺: 506.1. Purity:91.6%. ¹H NMR (400 MHz, DMSO): δ 8.58-8.55 (m, 1H), 8.31 (s, 1H), 8.24(d, J=7.4 Hz, 1H), 8.19-8.17 (m, 2H), 7.95 (s, 1H), 7.84 (s, 1H), 7.62(s, 1H), 7.26 (s, 1H), 6.73-6.70 (m, 1H), 5.35 (s, 2H), 4.54 (d, J=5.7Hz, 2H), 2.40 (s, 3H), 1.85-1.81 (m, 1H), 0.89-0.87 (m, 2H), 0.58-0.56(m, 2H).

Example 18

Synthesis of 2-(chloromethyl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine

A solution of 5-(trifluoromethyl)pyridin-2-amine (500 mg, 3.1 mmol) and1,3-dichloropropan-2-one (1.2 g, 9.3 mmol) in DMF (15 mL) was stirred at95° C. for 13 h. The reaction was quenched with aqueous NaHCO₃ solution(20 mL) and extracted with EtOAc (30 mL×3). The combined organic layerswere washed with brine, dried over Na₂SO₄, concentrated in vacuo to givethe crude, which was purified with silica gel chromatography (PE/EA=1/2)to give the 2-(chloromethyl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine(350 mg, yield: 48%) as a yellow solid. ESI-MS [M+H]⁺: 235.2.

Synthesis ofN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(I-18)

A mixture of 2-(chloromethyl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine(200 mg, 0.85 mmol),N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide(234 mg, 0.85 mmol) and Cs₂CO₃ (831 mg, 2.55 mmol) in DMF (10 mL) wasstirred at 55° C. for 2 h. H₂O (30 mL) was added to the reaction andextracted with EtOAc (30 mL×3). The combined organic layers were washedwith brine, dried over Na₂SO₄ and concentrated in vacuo to give thecrude, which was purified by prep-TLC (DCM/MeOH=10/1) to give theN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(25 mg, yield: 6.2%) as a white solid. ESI-MS [M+H]⁺: 474.2. Purity:99.7%. ¹H NMR (400 MHz, MeOD): δ 8.99 (s, 1H), 8.27 (s, 1H), 8.19-8.17(m, 2H), 7.93 (s, 2H), 7.75 (s, 1H), 7.66 (d, J=9.5 Hz, 1H), 7.50 (dd,J=9.5, 1.5 Hz, 1H), 6.63 (dd, J=7.5, 1.9 Hz, 1H), 5.52 (s, 2H), 4.70 (s,2H).

Example 19

Synthesis ofN-((7-bromoimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(I-19)

A mixture of 2-(chloromethyl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine(200 mg, 0.85 mmol),N-((7-bromoimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide(271 mg, 0.85 mmol) and Cs₂CO₃ (831 mg, 2.55 mmol) in DMF (10 mL) wasstirred at 55° C. for 2 h. H₂O (30 mL) was added to the reaction andextracted with EtOAc (30 mL×3). The combined organic layers were washedwith brine, dried over Na₂SO₄ and concentrated in vacuo to give thecrude, which was purified by prep-TLC (DCM/MeOH=10/1) to give theN-((7-bromoimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(40 mg, yield: 9%) as a white solid. ESI-MS [M+H]⁺: 518.0. Purity:94.14%. ¹H NMR (400 MHz, MeOD): δ 8.99 (s, 1H), 8.27 (s, 1H), 8.19 (s,1H), 8.11 (d, J=7.4 Hz, 1H), 7.94 (s, 3H), 7.66 (d, J=9.5 Hz, 1H), 7.50(d, J=9.5 Hz, 1H), 6.75-6.67 (m, 1H), 5.52 (s, 2H), 4.70 (s, 2H).

Example 20

Synthesis of 5-cyclopropyl-4-fluoropyridin-2-amine

A mixture of 5-bromo-4-fluoropyridin-2-amine (1 g, 5.2 mmol),cyclopropylboronic acid (675 mg, 7.9 mmol), Pd(AcO)₂ (116 mg, 0.52mmol), PCy₃ (280 mg, 1 mmol) and K₃PO₄ (3.3 g, 15.6 mmol) in toluene/H₂O(50 mL/5 mL) was stirred in a sealed tube at 105° C. under N₂ for 12 h.The reaction was concentrated to give the crude, which was purified bysilica gel chromatography (PE/EA=1/1) to give the5-cyclopropyl-4-fluoropyridin-2-amine (500 mg, yield: 64%) as a whitesolid. ESI-MS [M+H]⁺: 153.2.

Synthesis of2-(chloromethyl)-6-cyclopropyl-7-fluoroimidazo[1,2-a]pyridine

A mixture of 5-cyclopropyl-4-fluoropyridin-2-amine (500 mg, 3.3 mmol)and 1,3-dichloropropan-2-one (1.25 g, 9.9 mmol) in DMF (30 mL) wasstirred at 95° C. for 13 h. The pH of the reaction was adjusted to 9 byaddition of aqueous NaHCO₃ and then extracted with EtOAc (50 mL×3). Thecombined organic layers were washed with brine, dried over Na₂SO₄, andconcentrated in vacuo to give the crude, which was purified with silicagel chromatography (PE/EA=3/1) to give the2-(chloromethyl)-6-cyclopropyl-7-fluoroimidazo[1,2-a]pyridine (150 mg,yield: 20%) as a yellow solid. ESI-MS [M+H]⁺: 225.1.

Synthesis of Ethyl1-((6-cyclopropyl-7-fluoroimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate

A mixture of2-(chloromethyl)-6-cyclopropyl-7-fluoroimidazo[1,2-a]pyridine (150 mg,0.67 mmol), ethyl 1H-pyrazole-4-carboxylate (103 mg, 0.74 mmol) andCs₂CO₃ (655 mg, 2.01 mmol) in DMF (10 mL) was stirred at 55° C. for 2 h.H₂O (30 mL) was added to the reaction and extracted with EtOAc (30mL×3). The combined organic layers were washed with brine, dried overNa₂SO₄, and concentrated in vacuo to give the crude, which was purifiedwith silica gel chromatography (DCM/MeOH=20/1) to give the ethyl1-((6-cyclopropyl-7-fluoroimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate(100 mg, yield: 45%) as yellow solid. ESI-MS [M+H]⁺: 329.2.

Synthesis of1-((6-cyclopropyl-7-fluoroimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylicAcid

To a solution of ethyl1-((6-cyclopropyl-7-fluoroimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate(100 mg, 0.31 mmol) in THF/EtOH/H₂O (4 mL/4 mL/2 mL) was added LiOH (22mg, 0.91 mmol). The resulting reaction was stirred at 80° C. for 1.5 h.Most of the solvent was removed. The pH of the residue was adjusted toaround 5 and a yellow solid was precipitate out. The mixture wasfiltered and the solid was dried to give the1-((6-cyclopropyl-7-fluoroimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylicacid (75 mg, yield: 81%) as a yellow solid. ESI-MS [M+H]⁺: 301.1.

Synthesis ofN-((7-bromoimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-7-fluoroimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(I-20)

To a solution of1-((6-cyclopropyl-7-fluoroimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylicacid (35 mg, 0.12 mmol), (7-bromoimidazo[1,5-a]pyridin-1-yl)methanamine(35 mg, 0.15 mmol) and HATU (68 mg, 0.18 mmol) in DMF (5 mL) was addedDIPEA (77 mg, 0.6 mmol). The resulting reaction was stirred at RT for 2h. Water (30 mL) was added and extracted with EtOAc (50 mL×2). Thecombined organic layers were washed with brine, dried over Na₂SO₄,concentrated in vacuo to give the crude, which was purified withprep-TLC (DCM/MeOH=10/1) to giveN-((7-bromoimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-7-fluoroimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(19 mg, yield: 32%). ESI-MS [M+H]⁺: 508.1. Purity: 90.5%. ¹H NMR (400MHz, MeOD): δ 8.26 (s, 1H), 8.18 (d, J=7.1 Hz, 1H), 8.13 (s, 1H), 8.10(d, J=7.4 Hz, 1H), 7.92 (s, 1H), 7.91 (s, 1H), 7.67 (s, 1H), 7.12 (d,J=10.3 Hz, 1H), 6.72 (d, J=7.4 Hz, 1H), 5.41 (s, 2H), 4.68 (s, 2H),2.04-1.87 (m, 1H), 1.02-0.97 (m, 2H), 0.76-0.72 (m, 2H).

Example 21

Synthesis ofN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-7-fluoroimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(I-21)

To a solution of1-((6-cyclopropyl-7-fluoroimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylicacid (35 mg, 0.12 mmol), (7-chloroimidazo[1,5-a]pyridin-1-yl)methanamine(28 mg, 0.15 mmol) and HATU (68 mg, 0.18 mmol) in DMF (5 mL) was addedDIPEA (77 mg, 0.6 mmol). The resulting reaction was stirred at RT for 2h. Water (30 mL) was added and extracted with EtOAc (50 mL×2). Thecombined organic layers were washed with brine, dried over Na₂SO₄,concentrated in vacuo to give the crude, which was purified withprep-TLC (DCM/MeOH=10/1) to giveN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-7-fluoroimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(20 mg, yield: 32%). ESI-MS [M+H]⁺: 464.1. Purity: 94.8%. ¹H NMR (400MHz, MeOD): δ 8.25 (s, 1H), 8.19-8.12 (m, 3H), 7.90 (s, 1H), 7.73 (s,1H), 7.68 (s, 1H), 7.13 (d, J=10.3 Hz, 2H), 6.62 (dd, J=7.5, 1.9 Hz,1H), 5.41 (s, 2H), 4.68 (s, 2H), 1.37 (dd, J=6.7, 3.3 Hz, 1H), 1.02-0.97(m, 2H), 0.75-0.71 (m, 2H).

Example 22

Synthesis of 6-cyclopropylpyridin-2-amine

To a solution of 2-amino-6-bromopyridine (1.0 g, 5.75 mmol) intoluene/H₂O (15 mL/3 mL) was added cyclopropylboronic acid (1.98 g, 23mmol), Palladium diacetate (134 mg, 0.63 mmol),2-dicyclohexylphosphino-2′, 6-dimethoxybihenyl (240 mg, 0.6 mmol) andpotassium phosphate (4.24 g, 20.12 mmol). The resulting mixture wasstirred at 90° C. for 16 h. The reaction was diluted with H₂O (20 mL),extracted with ethyl acetate (3×50 mL), The combined organic layers werewashed with brine, dried over anhydrous sodium sulfate and concentrated.The residue was purified by flash column chromatography to give6-cyclopropylpyridin-2-amine (621 mg, yield: 81%). ESI-MS [M+H]⁺: 135.2.

Synthesis of 2-(chloromethyl)-5-cyclopropylimidazo[1,2-a]pyridine

To a solution of 5-cyclopropylpyrimidin-2-amine (600 mg, 4.5 mmol) inN,N-dimethylformamine (2 mL) was added 1,3-dichloropropan-2-one (2.2 g,18.0 mmol). The resulting mixture was stirred at 80° C. for 2.5 h. Thereaction mixture was quenched with H₂O (50 mL) and extracted with ethylacetate (3×30 mL), The organic layer was washed with brine, dried overanhydrous sodium sulfate and concentrated. The residue was purified byflash column chromatography to give2-(chloromethyl)-5-cyclopropylimidazo[1,2-a]pyridine (300 mg, yield:33%). ESI-MS [M+H]⁺: 207.1.

Synthesis of Ethyl1-((5-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate

To a solution of 2-(chloromethyl)-5-cyclopropylimidazo[1,2-a]pyridine(150 mg, 0.73 mmol) in N,N-dimethylformamine (2 mL) was added cesiumcarbonate (949 mg, 2.92 mmol) and ethyl 1H-pyrazole-4-carboxylate (102mg, 0.73 mmol). The resulting mixture was stirred at RT for 3 h. Water(50 mL) was added and extracted with ethyl acetate (3×30 mL). Theorganic layers were washed with brine, dried over anhydrous sodiumsulfate and concentrated. The residue was purified by flash columnchromatography to give ethyl1-((5-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate(220 mg, yield: 80%). ESI-MS [M+H]⁺: 311.2.

Synthesis of1-((5-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylicAcid

To a solution of ethyl1-((5-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate(210 mg, 0.68 mmol) in a mixture solvent of THF/EtOH/H₂O (3 mL/3 mL/1.5mL) was added lithium hydroxide (82 mg, 3.39 mmol). The resultingmixture was stirred at 80° C. for 1.5 h. Water (50 mL) was added and thepH of the mixture was adjusted to 4-5 by adding HCl solution. Themixture was then extracted with DCM (3×30 mL), The organic layers werewashed with brine, dried over anhydrous sodium sulfate, and concentratedto give1-((5-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylicacid (140 mg, Yield: 60%) which was used in the next step withoutfurther purification. ESI-MS [M+H]⁺: 283.1.

Synthesis ofN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((5-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(I-22)

To the solution of1-((5-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylicacid (67 mg, 0.21 mmol) in dry DMF (3 mL) was added HATU (116 mg, 0.305mmol), DIPEA (16 mg, 0.125 mmol) and(7-chloroimidazo[1,5-a]pyridin-1-yl)methanamine (44 mg, 0.24 mmol) atRT. The reaction was stirred at RT for 2 h. Water (30 mL) was added andthe mixture was extracted with ethyl acetate (20 mL×3). The combinedorganic layer was washed with brine, dried over anhydrous sodium sulfateand concentrated. The residue was purified by prep-HPLC to giveN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((5-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(36 mg, yield: 30%) as a white solid. ESI-MS [M+H]⁺: 446.2. Purity:98.74. ¹H NMR (400 MHz, DMSO): δ 8.59 (t, J=5.6 Hz, 1H), 8.34-8.26 (m,2H), 8.25 (s, 1H), 8.02 (s, 1H), 7.86 (s, 1H), 7.78 (s, 1H), 7.41 (d,J=9.0 Hz, 1H), 7.24-7.14 (m, 1H), 6.72-6.61 (m, 2H), 5.45 (s, 2H), 4.55(d, J=5.8 Hz, 2H), 2.18 (s, 1H), 1.13-1.1.02 (m, 2H), 0.83-0.74 (m, 2H).

Example 23

Synthesis of 6-chloro-5-cyclopropylpyridin-2-amine

A mixture of 5-bromo-6-chloropyridin-2-amine (3 g, 14 mmol) andcyclopropyl boronic acid (2.4 g, 28 mmol), Pd(OAc)₂ (313.6 mg, 1.4mmol), tricyclohexylphosphene (784 mg, 2.8 mmol) and K₃PO₄ (5.9 g, 28mmol) in dioxane/H₂O (20 mL/20 mL) was stirred in a sealed tube at 100°C. under N₂ for 16 h. The reaction was concentrated to give the crude,which was purified by silica gel chromatography (PE/EA=5/1) to give the6-chloro-5-cyclopropylpyridin-2-amine (2.4 g, yield: 98%) as a whitesolid. ESI-MS [M+H]+: 169.2.

Synthesis of5-chloro-2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine

A mixture of 6-chloro-5-cyclopropylpyridin-2-amine (2.4 g, 14.2 mmol)and 1,3-dichloropropan-2-one (7.16 g, 56.8 mmol) in ethanol (30 mL) wasstirred at 78° C. for 16 h. The mixture was quenched with saturatedNaHCO₃ (50 mL) and extracted with DCM (100 mL×3). The combined organiclayers were concentrated and purified by flash column silica gelchromatography (DCM/MeOH=15/1) to give the5-chloro-2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine (1.8 g,yield: 53%) as a yellow solid. ESI-MS [M+H]+: 241.1.

Synthesis of Ethyl1-((5-chloro-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate

To a solution of5-chloro-2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine (800 mg,3.33 mmol) in dry DMF (10 mL) was added ethyl 1H-pyrazole-4-carboxylate(512.4 mg, 3.66 mmol) and Cs₂CO₃ (3.25 g, 10 mmol). Then the reactionmixture was stirred at 55° C. for 16 h under N₂ atmosphere. The mixturewas cooled to RT, diluted with H₂O (20 mL) and extracted with ethylacetate (30 mL×3). The combined organic layers were washed with brine(20 mL×2), dried over anhydrous sodium sulfate and concentrated invacuo. The residue was purified by flash chromatography on silica gel(DCM/MeOH=10/1) to give the ethyl1-((5-chloro-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate(870 mg, yield: 76%) as a white solid. ESI-MS [M+H]⁺: 345.2.

Synthesis of1-((5-chloro-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylicAcid

To a solution of ethyl1-((5-chloro-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate(300 mg, 0.87 mmol) in THF (5 mL) and H₂O (5 mL) was added LiOH.H₂O (110mg, 2.62 mmol), then the reaction mixture was stirred at 50° C. for 16h. The solvent was removed. and the pH of the residue was adjusted toaround 5 by adding 1 M HCl solution allowing a yellow solid wasprecipitate out. The mixture was filtered and the solid was dried togive the1-((5-chloro-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylicacid (175 mg, yield: 64%) as a white solid. ESI-MS [M+H]⁺: 317.1.

Synthesis of1-((5-chloro-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide(I-23)

To a solution of1-((5-chloro-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylicacid (100 mg, 0.32 mmol) in dry DMF (3 mL) was added(7-chloroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride (69.4 mg,0.32 mmol), HATU (182 mg, 0.48 mmol) and DIPEA (124 mg, 0.96 mmol), thereaction mixture was stirred at RT for 16 h. The reaction mixturediluted with H₂O (20 mL), extracted with ethyl acetate (30 mL×3). Thecombined organic layers were washed with brine (20 mL×2), dried overanhydrous sodium sulfate and concentrated in vacuo. The residue waspurified by prep-TLC (DCM/MeOH=10/1) to afford1-((5-chloro-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide(15 mg, yield: 9.8%) as a white solid. ESI-MS [M+H]⁺: 480.1. Purity:90.37%. ¹H NMR (400 MHz, DMSO-d6): δ 8.58 (t, J=5.5 Hz, 1H), 8.30 (d,J=6.8 Hz, 2H), 8.24 (s, 1H), 7.92 (s, 1H), 7.86 (s, 1H), 7.78 (s, 1H),7.50 (d, J=9.3 Hz, 1H), 6.98 (d, J=9.3 Hz, 1H), 6.64 (d, J=7.5, 1.9 Hz,1H), 5.46 (d, J=9.6 Hz, 2H), 4.55 (d, J=5.6 Hz, 2H), 2.19-2.06 (m, 1H),1.03 (m, 2H), 0.78 (m, 2H).

Example 24

Synthesis of 4-chloro-5-cyclopropylpyridin-2-amine

A mixture of 5-bromo-4-chloropyridin-2-amine (3.24 g, 15.6 mmol),cyclopropylboronic acid (2.01 g, 23.4 mmol), Pd(OAc)₂ (350 mg, 1.56mmol), K₃PO₄ (6.62 g, 31.2 mmol) and PCy₃ (875 mg, 3.12 mmol) in toluene(40 mL) and H₂O (5 mL) was stirred at 80° C. overnight. Water (100 mL)was added and the mixture was extracted with EtOAc (100 mL×3). Thecombined organics were concentrated and purified by silica gelchromatography (EA/PE=2:3 to 10:1) to give4-chloro-5-cyclopropylpyridin-2-amine (1.89 g, yield: 18.7%) as a yellowsolid. ESI-MS [M+H]⁺: 169.1.

Synthesis of7-chloro-2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine

To a solution of 4-chloro-5-cyclopropylpyridin-2-amine (1.2 g, 7.1 mmol)in DMF (20 mL) was added 1,3-dichloropropan-2-one (1.8 g, 14.2 mmol) atRT. After the mixture was stirred at 100° C. for 2 h, H₂O (50 mL) wasadded and extracted with EtOAc (100 mL×3). The combined organic layerswere concentrated and purified by silica gel chromatography (EA/PE=1:10to 3:7) to give7-chloro-2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine (674 mg,yield: 38%) as a yellow solid. ESI-MS [M+H]⁺: 241.1.

Synthesis of Ethyl1-((7-chloro-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate

A mixture of7-chloro-2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine (480 mg,2.0 mmol), ethyl 1H-pyrazole-4-carboxylate (689 mg, 4.92 mmol) andCs₂CO₃ (2.4 g, 7.38 mmol) in DMF (10 mL) was stirred at 60° C. for 3 h.Water (50 mL) was added and the mixture was extracted with EtOAc (50mL×3). The combined organic layers were washed with brine, dried overNa₂SO₄, filtered and concentrated to give the crude, which was purifiedby silica gel chromatography (EA/PE=7:3 to 10:1) to ethyl1-((7-chloro-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate(390 mg, yield: 57%) as a white solid. ESI-MS [M+H]⁺: 345.1.

Synthesis of1-((7-chloro-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylicAcid

To a solution of ethyl1-((7-chloro-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate(200 mg, 0.58 mmol) in ethanol/THF/H₂O (3 mL/3 mL/1.5 mL) was addedLiOH.H₂O (97 mg, 2.32 mmol). The reaction mixture was stirred at 65° C.for 3 h. The mixture was then concentrated and then diluted with H₂O (20mL). The pH of the aqueous layer was adjust to 4 by adding 1 M HClsolution and extracted with EtOAc (50 mL×3). The combined organic layerswere concentrated to give crude1-((7-chloro-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylicacid (230 mg) as a white solid, which was used in the next step withoutfurther purification. ESI-MS [M+H]⁺: 317.1.

Synthesis of1-((7-chloro-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide(I-24)

A mixture of crude1-((7-chloro-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylicacid (230 mg, 0.73 mmol),(7-chloroimidazo[1,5-a]pyridin-1-yl)methanamine (65.1 mg, 0.3 mmol),HATU (278 mg, 0.73 mmol) and DIPEA (375 mg, 2.9 mmol) in DMF (5 mL) wasstirred at RT for 3 h. Water (30 mL) was added and the mixture wasextracted with EtOAc (50 mL×3). The combined organic layers wereconcentrated and purified by prep-TLC (DCM:MeOH=8:1) to give1-((7-chloro-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide(11.1 mg, yield: 7.7%) as a white solid. ESI-MS [M+H]⁺: 480.0. Purity:98.15%. ¹H NMR (400 MHz, DMSO): δ 8.58 (t, J=5.3 Hz, 1H), 8.40 (s, 1H),8.31-8.30 (m, 2H), 8.20 (s, 1H), 7.86 (s, 1H), 7.78 (s, 1H), 7.72 (s,1H), 7.68 (s, 1H), 6.65 (dd, J=7.4, 1.8 Hz, 1H), 5.40 (s, 2H), 4.55 (d,J=5.6 Hz, 2H), 1.98-1.94 (m, 1H), 0.95-0.94 (m, 2H), 0.66-0.65 (m, 2H).

Example 25

Synthesis ofN-((7-bromoimidazo[1,5-a]pyridin-1-yl)methyl)-1-((7-chloro-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(I-25)

A mixture of crude1-((7-chloro-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylicacid (230 mg, 0.73 mmol), (7-bromoimidazo[1,5-a]pyridin-1-yl)methanamine(67.8 mg, 0.3 mmol), HATU (278 mg, 0.73 mmol) and DIPEA (375 mg, 2.9mmol) in DMF (5 mL) was stirred at RT for 3 h. Water (30 mL) was addedand the mixture was extracted with EtOAc (50 mL×3). The combined organiclayers were concentrated and purified by prep-TLC (DCM:MeOH=8:1) to giveN-((7-bromoimidazo[1,5-a]pyridin-1-yl)methyl)-1-((7-chloro-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(31.5 mg, yield: 20%) as a white solid. ESI-MS [M+H]⁺: 524.0. Purity:97%. ¹H NMR (400 MHz, DMSO): δ 8.58-8.57 (m, 1H), 8.39 (s, 1H), 8.31 (s,1H), 8.23-8.20 (m, 2H), 7.94 (s, 1H), 7.85 (s, 1H), 7.69 (d, J=13.8 Hz,2H), 6.72-6.71 (m, 1H), 5.39 (s, 2H), 4.54 (s, 2H), 1.95-1.93 (m, 1H),0.94-0.93 (m, 2H), 0.65-0.64 (m, 2H).

Example 26

Synthesis ofN-((7-bromoimidazo[1,5-a]pyridin-1-yl)methyl)-1-((5,6-dimethylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(I-26)

To the solution of1-((5,6-dimethylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylicacid (54 mg, 0.2 mmol) in dry DMF (3 mL) was added HATU (114 mg, 0.3mmol), DIPEA (129 mg, 1.0 mmol) and(7-bromoimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride (52.4 mg,0.2 mmol) at RT. The reaction was stirred at RT for 2 h. Water (30 mL)was added and the mixture was extracted with ethyl acetate (30 mL×3).The combined organic layers were washed with brine, dried over anhydroussodium sulfate and concentrated. The residue was purified by prep-HPLCto giveN-((7-bromoimidazo[1,5-a]pyridin-1-yl)methyl)-1-((5,6-dimethylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(9.7 mg, yield: 10.2%). ESI-MS [M+H]⁺: 478.1. Purity: 90.33%. ¹H NMR(400 MHz, DMSO): δ 8.58 (t, J=5.6 Hz, 1H), 8.31 (s, 1H), 8.28-8.18 (m,2H), 7.95 (s, 1H), 7.85 (s, 1H), 7.76 (s, 1H), 7.33 (d, J=9.1 Hz, 1H),7.14 (d, J=9.2 Hz, 1H), 6.76-6.67 (m, 1H), 5.40 (s, 2H), 4.54 (d, J=5.7Hz, 2H), 2.49 (s, 3H), 2.29 (s, 3H).

Example 27

Synthesis of 5-bromo-2-(chloromethyl)imidazo[1,2-a]pyridine

To a solution of 6-bromopyridin-2-amine (800 mg, 4.6 mmol) inN,N-dimethylformamine (5 mL) was added 1,3-dichloropropan-2-one (3.05 g,24.0 mmol). The resulting mixture was stirred at 90° C. for 2.5 h. Thereaction mixture was diluted with H₂O (50 mL) and extracted with ethylacetate (3×30 mL). The organic layers were washed with brine, dried overanhydrous sodium sulfate and concentrated. The residue was purified byflash column chromatography to give5-bromo-2-(chloromethyl)imidazo[1,2-a]pyridine (600 mg, yield: 53%).ESI-MS [M+H]⁺: 245.0.

Synthesis of Ethyl1-((5-bromoimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate

To a solution of 5-bromo-2-(chloromethyl)imidazo[1,2-a]pyridine (200 mg,0.82 mmol) in N,N-dimethylformamine (3 mL) was added cesium carbonate(1.1 g, 3.28 mmol) and ethyl 1H-pyrazole-4-carboxylate (115 mg, 0.82mmol). The resulting mixture was stirred at RT for 2 h then diluted withH₂O (50 mL) and extracted with ethyl acetate (3×30 mL). The organiclayers were washed with brine, dried over anhydrous sodium sulfate andconcentrated. The residue was purified by flash column chromatography togive ethyl1-((5-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate(236 mg, yield: 83%). ESI-MS [M+H]⁺: 349.0.

Synthesis of1-((5-bromoimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylicAcid

To a solution of ethyl1-((5-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate(236 mg, 0.68 mmol) in the mixture of THF/H₂O (3 mL/3 mL) was addedlithium hydroxide (82 mg, 3.4 mmol). The resulting mixture was stirredat 80° C. for 2 h. THF was evaporated and the pH of the H₂O phase wasadjusted to 5 by adding 1 M HCl solution. The resulting solidprecipitate was filtered to give1-((5-bromoimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylicacid (131 mg, Yield: 60%), which was used in the next step withoutfurther purification. ESI-MS [M+H]⁺: 321.0.

Synthesis of1-((5-bromoimidazo[1,2-a]pyridin-2-yl)methyl)-N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide(I-27)

To the solution of1-((5-bromoimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylicacid (65 mg, 0.20 mmol) in dry DMF (3 mL) was added HATU (116 mg, 0.305mmol), DIPEA (131 mg, 1.02 mmol) and(7-chloroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride (44 mg,0.20 mmol) at RT. The reaction was stirred at RT for 2 h. Water (30 mL)was added and the mixture was extracted with ethyl acetate (20 mL×3).The combined organic layers were washed with brine, dried over anhydroussodium sulfate and concentrated. The residue was purified by prep-HPLCto give1-((5-bromoimidazo[1,2-a]pyridin-2-yl)methyl)-N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide(41 mg, yield: 37%). ESI-MS [M+H]⁺: 484.0. Purity: 100%. ¹H NMR (400MHz, DMSO): δ 8.60 (t, J=5.6 Hz, 1H), 8.39 (s, 1H), 8.32 (d, J=7.5 Hz,1H), 8.26 (s, 1H), 7.97 (s, 1H), 7.88 (s, 1H), 7.81 (s, 1H), 7.61 (d,J=8.8 Hz, 1H), 7.33 (d, J=7.2 Hz, 1H), 7.31-7.21 (m, J=8.7, 7.4 Hz, 1H),6.72-6.63 (m, 1H), 5.48 (s, 2H), 4.57 (d, J=5.7 Hz, 2H).

Example 28

Synthesis of 6-bromo-2-(chloromethyl)-7-methylimidazo[1,2-a]pyridine

To a solution of 5-bromo-4-methylpyridin-2-amine (1000 mg, 5.37 mmol) inDMF (15 mL) was added 1,3-dichloropropan-2-one (2.04 g, 16.1 mmol) atRT. The resulting reaction was stirred at 85° C. for 2 h. The solutionwas quenched with H₂O (40 mL) and the pH of the mixture was adjusted to8 by adding saturated a NaHCO₃ solution. The resulting mixture was thenextracted with EtOAc (50 mL×3). The combined organic layers were washedwith brine, dried over Na₂SO₄ and concentrated in vacuo to give thecrude, which was purified with a silica gel column (PE/EtOAc=1/1) togive the 6-bromo-2-(chloromethyl)-7-methylimidazo[1,2-a]pyridine (500mg, yield: 36%) as a light yellow oil. ESI-MS [M+H]⁺: 259.2.

Synthesis of1-((6-bromo-7-methylimidazo[1,2-a]pyridin-2-yl)methyl)-N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide(I-28)

To a solution 6-bromo-2-(chloromethyl)-7-methylimidazo[1,2-a]pyridine(56 mg, 0.22 mmol) in DMF (3 mL) was addedN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide(40 mg, 0.14 mmol) and Cs₂CO₃ (140 mg, 0.43 mmol) at RT. The resultingreaction was stirred at RT for 12 h. H₂O (30 mL) was added to thereaction and extracted with EtOAc (30 mL×3). The combined organic layerswere washed with brine, dried over Na₂SO₄ and concentrated in vacuo togive the crude, which was purified with prep-TLC (DCM/MeOH=10/1) to givethe 1-((6-bromo-7-methylimidazo[1,2-a]pyridin-2-yl)methyl)-N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide(22 mg, yield: 32%) as a white solid. ESI-MS [M+H]⁺: 498.0. Purity:98.7%. ¹H NMR (400 MHz, DMSO): δ 8.89 (s, 1H), 8.60-8.57 (m, 1H),8.31-8.29 (m, 2H), 8.22 (s, 1H), 7.87 (s, 1H), 7.78 (s, 1H), 7.72 (s,1H), 7.51 (s, 1H), 6.65 (d, J=7.4 Hz, 1H), 5.40 (s, 2H), 4.55 (d, J=5.6Hz, 2H), 2.36 (s, 3H).

Example 29

Synthesis ofN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide

A mixture of 1H-pyrrolo[3,2-b]pyridine-3-carboxylic acid (100 mg, 0.62mmol), 7-chloroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride (160mg, 0.74 mmol), HATU (290 mg, 0.78 mmol) and DIPEA (0.32 mL, 1.86 mmol)in DMF (5 mL) was stirred at RT for 16 h. Water (30 mL) was added andextracted with EtOAc (30 mL×3). The combined organic layers wereconcentrated and purified by prep-TLC (DCM/MeOH=10/1) to giveN-((7-bromoimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-5-methylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(60 mg, yield: 30%) as a yellow solid. ESI-MS [M+H]⁺: 326.1.

Synthesis ofN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide(I-29)

A mixture ofN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide(50 mg, 0.15 mmol), 2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine(40 mg, 0.19 mmol) and Cs₂CO₃ (125 mg, 0.39 mmol) in DMF (5 mL) wasstirred at RT for 4 h. Water (30 mL) was added and extracted with EtOAc(30 mL×3). The combined organic layers were concentrated and purified byprep-HPLC to giveN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide(9.1 mg, yield: 12%) as a yellow solid. ESI-MS [M+H]⁺: 496.1. Purity:86.0%. ¹H NMR (400 MHz, DMSO): δ 9.06 (t, J=5.8 Hz, 1H), 8.43 (d, J=4.7Hz, 1H), 8.40-8.25 (m, 4H), 8.14 (d, J=8.3 Hz, 1H), 7.87 (s, 1H), 7.73(s, 1H), 7.37 (d, J=9.4 Hz, 1H), 7.26 (dd, J=8.3, 4.7 Hz, 1H), 6.97 (d,J=9.4 Hz, 1H), 6.66 (dd, J=7.4, 2.0 Hz, 1H), 5.59 (s, 2H), 4.77 (d,J=5.7 Hz, 2H), 1.96-1.81 (m, 1H), 0.96-0.83 (m, 2H), 0.73-0.56 (m, 2H).

Example 30

Synthesis ofN-((7-bromoimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide

A mixture of 1H-pyrrolo[3,2-b]pyridine-3-carboxylic acid (100 mg, 0.62mmol), 7-bromoimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride (190mg, 0.74 mmol), HATU (350 mg, 0.93 mmol) and DIPEA (0.32 mL, 1.86 mmol)in DMF (5 mL) was stirred at RT for 16 h. Water (30 mL) was added andthe mixture was extracted with EtOAc (30 mL×3). The combined organiclayers were concentrated and purified by prep-TLC (DCM/MeOH=10/1) togiveN-((7-bromoimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide(60 mg, yield: 20%) as a yellow solid. ESI-MS [M+H]⁺: 370.1.

Synthesis ofN-((7-bromoimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide(I-30)

A mixture ofN-((7-bromoimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide(60 mg, 0.16 mmol), 2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine(40 mg, 0.19 mmol) and Cs₂CO₃ (125 mg, 0.39 mmol) in DMF (5 mL) wasstirred at RT for 4 h. Water (30 mL) was added and the mixture wasextracted with EtOAc (30 mL×3). The combined organic layers wereconcentrated and purified by prep-HPLC to giveN-((7-bromoimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide(13.0 mg, yield: 15%) as a yellow solid. ESI-MS [M+H]⁺: 540.1. Purity:89.1%. ¹H NMR (400 MHz, DMSO): δ 9.06 (t, J=6.0 Hz, 1H), 8.43 (d, J=3.7Hz, 1H), 8.36 (d, J=5.4 Hz, 2H), 8.31-8.22 (m, 2H), 8.14 (d, J=8.0 Hz,1H), 8.04 (s, 1H), 7.73 (s, 1H), 7.37 (d, J=9.2 Hz, 1H), 7.26 (dd,J=8.3, 4.7 Hz, 1H), 6.97 (d, J=9.5 Hz, 1H), 6.81-6.67 (m, 1H), 5.59 (s,2H), 4.77 (d, J=5.8 Hz, 2H), 1.89 (d, J=5.1 Hz, 1H), 0.96-0.84 (m, 2H),0.64 (d, J=5.1 Hz, 2H).

Example 31

Synthesis of Methyl2-((dimethylamino)methylene)-4-methoxy-3-oxobutanoate

A mixture of methyl 4-methoxy-3-oxobutanoate (500 mg, 3.42 mmol) andDMF-DMA (410 mg, 3.42 mmol) in dry DMF (5 mL) was stirred at 110° C. for10 h. The mixture was concentrated to give methyl2-((dimethylamino)methylene)-4-methoxy-3-oxobutanoate (600 mg, yield:87%) as a yellow oil. ESI-MS [M+H]⁺: 202.1.

Synthesis of Methyl 3-(methoxymethyl)-1H-pyrazole-4-carboxylate

A solution of methyl2-((dimethylamino)methylene)-4-methoxy-3-oxobutanoate (600 mg, 3.0mmol), N₂H₄.H₂O (0.15 mL, 3.0 mmol) and AcOH (0.21 mL, 3.6 mmol) in dryEtOH (10 mL) was stirred at reflux for 12 h. The mixture wasconcentrated and purified by prep-TLC (DCM/MeOH=30/1) to give methyl3-(methoxymethyl)-1H-pyrazole-4-carboxylate (400 mg, yield: 78%) as abrown solid. ESI-MS [M+H]⁺: 171.1.

Synthesis of Methyl1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-3-(methoxymethyl)-1H-pyrazole-4-carboxylateand methyl1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-5-(methoxymethyl)-1H-pyrazole-4-carboxylate

A mixture of methyl 3-(methoxymethyl)-1H-pyrazole-4-carboxylate (100 mg,0.59 mmol), 2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine (150mg, 0.70 mmol) and Cs₂CO₃ (480 mg, 1.48 mmol) in DMF (5 mL) was stirredat RT for 16 h. Water (50 mL) was added and the mixture was extractedwith EtOAc (50 mL×3). The combined organic layers were concentrated andpurified by prep-TLC (DCM/MeOH=15/1) to give methyl1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-3-(methoxymethyl)-1H-pyrazole-4-carboxylate(100 mg, yield: 50.0%) as a light yellow solid. ESI-MS [M+H]⁺: 341.1 andmethyl1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-5-(methoxymethyl)-1H-pyrazole-4-carboxylate(50 mg, yield: 25.0%) as a light yellow solid. ESI-MS [M+H]⁺: 341.1.

Synthesis of1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-3-(methoxymethyl)-1H-pyrazole-4-carboxylicAcid

A solution of methyl1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-3-(methoxymethyl)-1H-pyrazole-4-carboxylate(100 mg, 0.29 mmol) and LiOH H₂O (40 mg, 0.88 mmol) in THF/MeOH/H₂O (2mL/2 mL/1 mL) was stirred at 70° C. for 1 h. Solvent was evaporated andthe pH value of the residue was adjusted to 5 by adding 1 M HClsolution. The resulting solid precipitate was filtered to give1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-3-(methoxymethyl)-1H-pyrazole-4-carboxylicacid (90 mg, yield: 94.7%) as a yellow oil which was used in the nextstep without purification. ESI-MS [M+H]⁺: 327.1.

Synthesis ofN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-3-(methoxymethyl)-1H-pyrazole-4-carboxamide(I-31)

A mixture of1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-3-(methoxymethyl)-1H-pyrazole-4-carboxylicacid (45 mg, 0.14 mmol), (7-chloroimidazo[1,5-a]pyridin-1-yl)methanamine(36 mg, 0.17 mmol), HATU (105 mg, 0.28 mmol) and DIPEA (0.1 mL, 0.41mmol) in DMF (3 mL) was stirred at RT for 2 h. Water (30 mL) was addedand the mixture was extracted with EtOAc (30 mL×3). The combined organiclayers were concentrated and purified by prep-TLC (DCM/MeOH=10/1) togiveN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-3-(methoxymethyl)-1H-pyrazole-4-carboxamide(19.6 mg, yield: 29%) as a white solid. ESI-MS [M+H]⁺: 490.1. Purity:97.6%. ¹H NMR (400 MHz, DMSO): δ 8.49 (s, 1H), 8.41-8.28 (m, 3H), 8.23(s, 1H), 7.90 (s, 1H), 7.79 (s, 1H), 7.55 (d, J=9.0 Hz, 1H), 7.29 (s,1H), 6.66 (d, J=6.3 Hz, 1H), 5.46 (s, 2H), 4.57 (d, J=5.2 Hz, 2H), 4.53(s, 2H), 3.20 (s, 3H), 1.99 (s, 1H), 0.97 (d, J=7.5 Hz, 2H), 0.71 (d,J=5.4 Hz, 2H).

Example 32

Synthesis of1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-5-(methoxymethyl)-1H-pyrazole-4-carboxylicAcid

A solution of methyl1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-5-(methoxymethyl)-1H-pyrazole-4-carboxylate(50 mg, 0.15 mmol) and LiOH H₂O (20 mg, 0.44 mmol) in THF/MeOH/H₂O (2mL/2 mL/1 mL) was stirred at 70° C. for 1 h. Solvent was evaporated andthe pH of the residue was adjusted to 5 by adding 1 M HCl solution.Solid precipitated and was filtered to give1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-5-(methoxymethyl)-1H-pyrazole-4-carboxylicacid (45 mg, yield: 94.7%) as a yellow oil. ESI-MS [M+H]⁺: 327.1.

Synthesis ofN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-5-(methoxymethyl)-1H-pyrazole-4-carboxamide(I-32)

A mixture of1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-3-(methoxymethyl)-1H-pyrazole-4-carboxylicacid (45 mg, 0.14 mmol), (7-chloroimidazo[1,5-a]pyridin-1-yl)methanamine(36 mg, 0.17 mmol), HATU (105 mg, 0.28 mmol) and DIPEA (0.1 mL, 0.41mmol) in DMF (5 mL) was stirred at RT for 2 h. Water (30 mL) was addedand the mixture was extracted with EtOAc (30 mL×3). The combined organiclayers were concentrated and purified by prep-TLC (DCM/MeOH=10/1) togiveN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-5-(methoxymethyl)-1H-pyrazole-4-carboxamide(40.0 mg, yield: 59%) as a white solid. ESI-MS [M+H]⁺: 490.1. Purity:99.2%. ¹H NMR (400 MHz, DMSO): δ 8.67 (s, 1H), 8.58 (s, 1H), 8.44-8.27(m, 2H), 8.02 (s, 1H), 7.94 (s, 1H), 7.81 (s, 1H), 7.67 (s, 1H), 7.52(s, 1H), 6.67 (d, J=7.2 Hz, 1H), 5.58 (s, 2H), 4.95 (s, 2H), 4.60 (d,J=5.5 Hz, 2H), 3.25 (s, 3H), 2.05 (d, J=16.1 Hz, 1H), 1.04 (t, J=18.0Hz, 2H), 0.74 (s, 2H).

Example 33

Synthesis of 3,4-dichloropicolinamide

To a solution of 2,2,6,6-tetramethylpiperidine (5.2 g, 37.2 mmol) indiethyl ether (80 mL) at 0° C. was added n-BuLi (2.4 M, 15.5 mL, 37.2mmol) dropwise. The resulting solution was stirred at 0° C. for 0.5 hand at −78° C. for 0.5 h. To this mixture was then slowly added asolution of 3,4-dichloropyridine (5 g, 33.8 mmol) in diethyl ether (10mL) dropwise. The resulting mixture was stirred at −78° C. for 2 hbefore the addition of isocyanotrimethylsilane (5.83 g, 50.7 mmol).After the addition, the cooling bath was removed and the reactionmixture was allowed to warm to RT over 1 h. The reaction mixture wasstirred at 25° C. for 16 h, H₂O (100 mL) was added, extracted with ethylacetate (100 mL×3), washed with brine (30 mL), dried over MgSO₄ andconcentrated in vacuo. The residue was suspended in 20 mL of diethylether and sonicated. The solid was collected through filtration andwashed with minimum amount of diethyl ether to give3,4-dichloropicolinamide (2.3 g, yield: 35%) as a yellow solid. ESI-MS[M+H]⁺: 191.1.

Synthesis of 3,4-dichloropicolinonitrile

To a solution of 3,4-dichloropicolinamide (500 mg, 2.63 mmol) in DMF (20mL) was added POCl₃ (2.4 g, 15.79 mmol) dropwise at 0° C. The mixturewas stirred at 25° C. for 16 h, then saturated NaHCO₃ (aq., 120 mL) wasadded and the reaction mixture was extracted with EtOAc (100 mL×3). Thecombined organic layers were washed with brine (100 mL), dried overNa₂SO₄, concentrated to give 3,4-dichloropicolinonitrile (420 mg, yield:93%) as a brown solid. ESI-MS [M+H]⁺: 173.0.

Synthesis of (3,4-dichloropyridin-2-yl)methanamine

To a mixture of LiAlH₄ (110 mg, 2.9 mmol) in dry THF (3 mL) was added3,4-dichloropicolinonitrile (200 mg, 1.16 mmol) in THF at −78° C. Themixture was stirred at −78° C. for 30 min, then stirred at −40° C. for30 min. The mixture was quenched with H₂O (10 mL), extracted with EtOAc(50 mL×3). The combined organic layers were washed with brine, driedover Na₂SO₄, concentrated to give (3,4-dichloropyridin-2-yl)methanamine(100 mg, yield: 49%) as a yellow oil. ESI-MS [M+H]⁺: 177.0.

Synthesis of N-((3,4-dichloropyridin-2-yl)methyl)formamide

The mixture of (3,4-dichloropyridin-2-yl)methanamine (100 mg, 0.57 mmol)in HCOOH (2 mL) was stirred at 90° C. for 3 h and then concentrated togive the crude. The crude was purified by prep-TLC (DCM/MeOH=10/1) togive N-((3,4-dichloropyridin-2-yl)methyl)formamide (70 mg, yield: 60%)as a yellow oil. ESI-MS [M+H]⁺: 205.1.

Synthesis of 7,8-dichloroimidazo[1,5-a]pyridine

The mixture of N-((3,4-dichloropyridin-2-yl)methyl)formamide (70 mg,0.34 mmol) in POCl₃ (2 mL) was stirred at 100° C. for 3 h. Then POCl₃was concentrated, H₂O (10 mL) was added, followed by saturated Na₂CO₃(20 mL). The mixture was extracted with EtOAc (50 mL*3) and the combinedorganic layers were washed with brine, dried over Na₂SO₄, andconcentrated to give the crude, which was purified by prep-TLC(PE/EA=1/2) to give 7,8-dichloroimidazo[1,5-a]pyridine (40 mg, yield:63%) as a yellow solid. ESI-MS [M+H]⁺: 187.0.

Synthesis of 7,8-dichloroimidazo[1,5-a]pyridine-1-carbaldehyde

To a solution of 7,8-dichloroimidazo[1,5-a]pyridine (100 mg, 0.54 mmol)in dry DMF (0.2 mL) was added POCl₃ (123 mg, 0.81 mmol) at 0° C. Themixture was stirred at 100° C. for 1 h then cooled and poured into iceH₂O. The mixture was basified with NH₄OH, extracted with DCM (50 mL×3)and concentrated to give the crude, which was purified by prep-TLC(DCM/MeOH=20/1) to give7,8-dichloroimidazo[1,5-a]pyridine-1-carbaldehyde (25 mg, yield: 22%) asa yellow solid. ESI-MS [M+H]⁺: 215.0.

Synthesis ofN-((7,8-dichloroimidazo[1,5-a]pyridin-1-yl)methyl)-2-methylpropane-2-sulfinamide

To a mixture of 7,8-dichloroimidazo[1,5-a]pyridine-1-carbaldehyde (25mg, 0.12 mmol) and 2-methylpropane-2-sulfinamide (17 mg, 0.14 mmol) indry THF (2 mL) was added tetraethoxytitanium (80 mg, 0.35 mmol). Themixture was stirred at 75° C. for 16 h and then cooled to 25° C. NaBH₄(18 mg, 0.47 mmol) was added and stirred at 25° C. for 3 h. The reactionwas quenched with H₂O (10 mL) and extracted with EtOAc (30 mL×3). Thecombined organic layers were washed with brine, dried over Na₂SO₄,concentrated to giveN-((7,8-dichloroimidazo[1,5-a]pyridin-1-yl)methyl)-2-methylpropane-2-sulfinamide(37 mg, yield: 100%) as a yellow solid. ESI-MS [M+H]⁺: 320.0.

Synthesis of (7,8-dichloroimidazo[1,5-a]pyridin-1-yl)methanamine

The mixture ofN-((7,8-dichloroimidazo[1,5-a]pyridin-1-yl)methyl)-2-methylpropane-2-sulfinamide(37 mg, 0.12 mmol) and HCl in dioxane (1 mL, 4 M) was stirred at 25° C.for 3 h. The resulting mixture was concentrated to give(7,8-dichloroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride (25mg, yield: 84%) as a yellow solid which was used in the next stepwithout purification. ESI-MS [M−16]: 199.0.

Synthesis ofN-((7,8-dichloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-methylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(I-33)

To a mixture of (7,8-dichloroimidazo[1,5-a]pyridin-1-yl)methanaminehydrochloride (25 mg, 0.1 mmol) and1-((6-methylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylicacid (25 mg, 0.1 mmol) in dry DMF (2 mL) was added DIPEA (64 mg, 0.5mmol) and HATU (76 mg, 0.2 mmol). The mixture was stirred at 25° C. for1 h. Water (20 mL) was added and extracted with EtOAc (30 mL×3). Thecombined organic phase was washed with brine, dried over Na₂SO₄, andconcentrated to give the crude, which was purified by prep-TLC(DCM/MeOH=10/1) to giveN-((7,8-dichloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-methylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(13.3 mg, yield: 30%) as a yellow solid. ESI-MS [M+H]⁺: 454.1. Purity:96.7%. ¹H NMR (400 MHz, DMSO): δ 8.44 (s, 1H), 8.35 (d, J=7.4 Hz, 1H),8.32-8.27 (m, 2H), 8.22 (s, 1H), 7.85 (s, 1H), 7.76 (s, 1H), 7.41 (d,J=9.2 Hz, 1H), 7.11 (d, J=9.2 Hz, 1H), 6.83 (d, J=7.4 Hz, 1H), 5.39 (s,2H), 4.80 (d, J=4.9 Hz, 2H), 2.25 (s, 3H).

Example 34

Synthesis of 5-chloro-6-ethylpyridin-2-amine

To a solution of 6-ethylpyridin-2-amine (1.0 g, 8.20 mmol) in dry DMF(16 mL) was added NCS (1.09 g, 8.2 mmol) at −10° C. and stirred at −10°C. for 2 h. The reaction mixture was diluted with H₂O (50 mL) andextracted with ethyl acetate (3×50 mL). The organic layers were washedwith brine, dried over anhydrous sodium sulfate and concentrated. Theresidue was purified by flash column chromatography to give5-chloro-6-ethylpyridin-2-amine (500 mg, yield: 39%). ESI-MS [M+H]⁺:157.1.

Synthesis of 6-chloro-2-(chloromethyl)-5-ethylimidazo[1,2-a]pyridine

To a solution of 5-chloro-6-ethylpyridin-2-amine (500 mg, 3.2 mmol) inN,N-dimethylformamine (3 mL) was added 1,3-dichloropropan-2-one (1.62 g,12.8 mmol). The resulting mixture was stirred at 90° C. for 2.5 h. Thereaction mixture was diluted with H₂O (50 mL), adjust to approximatelypH 9 by adding saturated NaHCO₃ solution, and then extracted with ethylacetate (3×30 mL). The organic layers were washed with brine, dried overanhydrous sodium sulfate and concentrated. The residue was purified byflash column chromatography to give6-chloro-2-(chloromethyl)-5-ethylimidazo[1,2-a]pyridine (390 mg, yield:37%). ESI-MS [M+H]⁺: 229.1.

Synthesis of Ethyl1-((6-chloro-5-ethylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate

To a solution of 6-chloro-2-(chloromethyl)-5-ethylimidazo[1,2-a]pyridine(250 mg, 1.11 mmol) in N,N-dimethylformamine (3 mL) was added cesiumcarbonate (1.80 g, 3.33 mmol) and ethyl 1H-pyrazole-4-carboxylate (155mg, 1.11 mmol). The resulting mixture was diluted with H₂O (30 mL) andextracted with ethyl acetate (3×30 mL). The organic layers were washedwith brine, dried over anhydrous sodium sulfate and concentrated. Theresidue was purified by flash column chromatography to give ethyl1-((6-chloro-5-ethylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate(360 mg, yield: 87%). ESI-MS [M+H]⁺: 333.1.

Synthesis of1-((6-chloro-5-ethylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylicAcid

To a solution of give ethyl1-((6-chloro-5-ethylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate(436 mg, 1.3 mmol) in a mixed solvent of THF/EtOH/H₂O (3 mL/3 mL/1 mL)was added lithium hydroxide (126 mg, 5.3 mmol). The resulting mixturewas stirred at 85° C. for 1.5 h and diluted with H₂O (15 mL). The pH ofthe mixture was then adjusted to 5 by adding 1 M HCl and then extractedwith DCM/MeOH (5/1, 3×50 mL). The combined organic layers wereconcentrated to give1-((6-chloro-5-ethylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylicacid (200 mg, yield: 50%), which was used in the next step withoutfurther purification. ESI-MS [M+H]⁺: 305.1.

Synthesis of1-((6-chloro-5-ethylimidazo[1,2-a]pyridin-2-yl)methyl)-N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide(I-34)

To the solution of1-((6-chloro-5-ethylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylicacid (65 mg, 0.21 mmol) in dry DMF (3 mL) was added HATU (120 mg, 0.32mmol), DIPEA (135 mg, 1.05 mmol) and(7-chloroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride (46 mg,0.21 mmol) at RT. The reaction was stirred at RT for 2 h. Water (30 mL)was added and the mixture was extracted with ethyl acetate (30 mL×3).The combined organic layers were washed with brine, dried over anhydroussodium sulfate and concentrated. The residue was purified by prep-HPLCto giveN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((5-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(41 mg, yield: 38%) as a white solid. ESI-MS [M+H]⁺: 468.0. Purity:100%. 1H NMR (400 MHz, DMSO): δ 8.59 (t, J=5.7 Hz, 1H), 8.34-8.26 (m,2H), 8.24 (s, 1H), 8.10 (s, 1H), 7.86 (s, 1H), 7.78 (s, 1H), 7.46 (d,J=9.5 Hz, 1H), 7.34 (d, J=9.5 Hz, 1H), 6.69-6.60 (m, 1H), 5.43 (s, 2H),4.55 (d, J=5.7 Hz, 2H), 3.20-3.10 (m, 2H), 1.20 (t, J=7.5 Hz, 3H).

Example 35

Synthesis of 4-chloro-3-methylpyridine 1-oxide

To a solution of 4-chloro-3-methylpyridine (5 g, 30.6 mmol) in dry DMF(100 mL) was added m-CPBA (10.8 g, 58.9 mmol). The reaction was stirredat RT for 3 h. The mixture was diluted with DCM (300 mL) and followed bysaturated NaHCO₃ (300 mL). Then the mixture was extracted with DCM (300mL×3). The combined organic layers were concentrated and purified bysilica gel chromatography (DCM/MeOH=15/1) to give4-chloro-3-methylpyridine 1-oxide (2.43 g, yield: 55.4%) as a whitesolid. ESI-MS [M+H]⁺: 144.2.

Synthesis of 4-chloro-3-methylpicolinonitrile

To a solution of 4-chloro-3-methylpyridine 1-oxide (2.43 g, 17.0 mmol),dimethylcarbamic chloride (1.92 g, 17.9 mmol) and TMSCN (2.02 g, 20.4mmol) in dry DMF (45 mL) was added Et₃N (4.7 mL, 34 mmol), the mixturewas stirred at 100° C. for 3 h. The reaction mixture was then quenchedwith saturated NaHCO₃ (200 mL) solution at 0° C. and extracted withEtOAc (100 mL×3). The combined organic layers were concentrated andpurified by silica gel chromatography (EA/PE=1/10) to give4-chloro-3-methylpicolinonitrile (1.87 g, yield: 72%) as a yellow oil.ESI-MS [M+H]⁺: 153.1.

Synthesis of (4-chloro-3-methylpyridin-2-yl)methanamine

To a solution of 4-chloro-3-methylpicolinonitrile (1.7 g, 11 mmol) indry THF (6 mL) was added BH₃-THF (1 M, 27.5 mL) at 0° C. The mixture wasstirred at 0° C. for 1 h and then stirred at RT overnight. The mixturewas quenched with MeOH and stirred at RT for 1 h, then concentrated togive (4-chloro-3-methylpyridin-2-yl)methanamine (2.1 g, crude) as ayellow solid which was used in the next step without purification.ESI-MS [M+H]⁺: 185.1.

Synthesis of N-((4-chloro-3-methylpyridin-2-yl)methyl)formamide

To a solution of 4-chloro-3-methylpicolinonitrile (2.1 g, 13.5 mmol) andformic acid (20 mL) was stirred at 80° C. for 3 h. The mixture wasconcentrated and purified by silica gel chromatography to giveN-((4-chloro-3-methylpyridin-2-yl)methyl)formamide (1.3 g, yield: 54%)as a brown oil. ESI-MS [M+H]⁺: 185.1.

Synthesis of 7-chloro-8-methylimidazo[1,5-a]pyridine

To a solution of N-((4-chloro-3-methylpyridin-2-yl)methyl)formamide (1.3g, 7 mmol) and POCl₃ (22 mL) was stirred at 110° C. for 2 h. POCl₃ wasremoved in vacuo. Water was added and followed by saturated Na₂CO₃(aq.). The mixture was extracted with EtOAc (100 mL×3). The combinedorganic layers were washed with brine, dried over Na₂SO₄, filtered andconcentrated to give the crude, which was purified by silica gelchromatography (EA/PE=1/1) to give7-chloro-8-methylimidazo[1,5-a]pyridine (700 mg, yield: 60%) as a brownsolid. ESI-MS [M+H]⁺: 167.1.

Synthesis of 7-chloro-8-methylimidazo[1,5-a]pyridine-1-carbaldehyde

A mixture of 7-chloro-8-methylimidazo[1,5-a]pyridine (660 mg, 3.96mmol), DMF (289.4 mg, 3.96 mmol) in POCl₃ (5 mL) was stirred at 100° C.for 1 h. Then the reaction mixture was poured to ice H₂O. NH₄OH solutionwas added to adjust pH to about 8 and then the mixture was extractedwith EtOAc (50 mL×3). The combined organic layers were concentrated andpurified by silica gel chromatography to give7-chloro-8-methylimidazo[1,5-a]pyridine-1-carbaldehyde (165 mg, yield:21%) as a white solid. ESI-MS [M+H]⁺: 195.1.

Synthesis ofN-((7-chloro-8-methylimidazo[1,5-a]pyridin-1-yl)methyl)-2-methylpropane-2-sulfinamide

A mixture of 7-chloro-8-methylimidazo[1,5-a]pyridine-1-carbaldehyde (154mg, 0.8 mmol), 2-methylpropane-2-sulfinamide (116.35 mg, 0.96 mmol) andTi(OEt)₄ (0.58 mL, 2.8 mmol) in THF (10 mL) was stirred at 80° C.overnight. After cooled to RT, NaBH₄ (151.32 mg, 4 mmol) was added. Thereaction mixture was stirred at RT for 3 h. The reaction was quenchedwith H₂O (20 mL) and extracted with EtOAc (50 mL×3). The combinedorganic layers were concentrated and purified by silica gelchromatography (DCM/CH₃OH=10:1) to giveN-((7-chloro-8-methylimidazo[1,5-a]pyridin-1-yl)methyl)-2-methylpropane-2-sulfinamide(87 mg, yield: 36%) as a yellow solid. ESI-MS [M+H]⁺: 300, and (131 mg,yield: 36%) as a yellow solid. ESI-MS [M+13]⁺: 312.

Synthesis of (7-chloro-8-methylimidazo[1,5-a]pyridin-1-yl)methanamine

To a solution ofN-((7-chloro-8-methylimidazo[1,5-a]pyridin-1-yl)methyl)-2-methylpropane-2-sulfinamide(187 mg, 0.62 mmol) in CH₃OH (8 mL) was added HCl (4 M in dioxane, 8mL). The mixture was stirred at RT for 1.5 h. Then concentrated to give(7-chloro-8-methylimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride(168 mg, crude) as a white solid which was used in the next step withoutpurification. ESI-MS [M−16]⁺: 179.1.

Synthesis ofN-((7-chloro-8-methylimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-methylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(I-35)

A mixture (7-chloro-8-methylimidazo[1,5-a]pyridin-1-yl)methanamine (44mg, 0.22 mmol),1-((6-methylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylicacid (57 mg, 0.22 mmol), HATU (167.2 mg, 0.44 mmol) and DIPEA (113.5 mg,0.88 mmol) in DMF (5 mL) was stirred at RT for 1.5 h. Water (30 mL) wasadded, extracted with EtOAc (30 mL×3), the combined organic phase werewashed with brine, dried over Na₂SO₄ and concentrated to give the crude,which was purified by silica gel chromatography (DCM/MeOH=10:1) to giveN-((7-chloro-8-methylimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-methylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(27 mg, yield: 28%) as a white solid. ESI-MS [M+H]⁺: 434.1. Purity:99.42%. ¹H NMR (400 MHz, DMSO): δ 8.33 (t, J=4.7 Hz, 1H), 8.26 (s, 2H),8.17 (s, 1H), 8.13 (d, J=7.3 Hz, 1H), 7.81 (s, 1H), 7.72 (s, 1H), 7.36(d, J=9.2 Hz, 1H), 7.08 (d, J=9.2 Hz, 1H), 6.59 (d, J=7.4 Hz, 1H), 5.33(s, 2H), 4.62 (d, J=4.9 Hz, 2H), 2.51 (s, 3H), 2.19 (s, 3H).

Example 36

Synthesis of 6-bromo-7-chloro-2-(chloromethyl)imidazo[1,2-a]pyridine

A mixture of 5-bromo-4-chloropyridin-2-amine (1.67 g, 9.9 mmol),1,3-dichloropropan-2-one (2.5 g, 19.8 mmol) in DMF (15 mL) was stirredat 90° C. for 5 h. The reaction mixture was diluted with H₂O (50 mL),adjusted to approximately pH 9 by adding saturated a NaHCO₃ solution,and extracted with ethyl acetate (3×30 mL). The combined organic layerswere concentrated and purified by silica gel chromatography (EA/PE=7:1)to give 6-bromo-7-chloro-2-(chloromethyl)imidazo[1,2-a]pyridine (900 mg,yield: 32%) as a yellow solid. ESI-MS [M+H]⁺: 278.9.

Synthesis of Ethyl1-((6-bromo-7-chloroimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate

A mixture of 6-bromo-7-chloro-2-(chloromethyl)imidazo[1,2-a]pyridine(560 mg, 2.0 mmol), ethyl 1H-pyrazole-4-carboxylate (560 mg, 4.0 mmol)and Cs₂CO₃ (1.95 g, 6.0 mmol) in DMF (10 mL) was stirred at 60° C. for 3h. The resulting mixture was diluted with H₂O (30 mL) and extracted withethyl acetate (3×30 mL), The combined organic layers were concentratedand purified by silica gel chromatography (EA/PE=10:1 to 7:13) to giveethyl1-((6-bromo-7-chloroimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate(400 mg, yield: 52%) as a white solid. ESI-MS [M+H]⁺: 383.0.

Synthesis of1-((6-bromo-7-chloroimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylicAcid

To a solution of ethyl1-((6-bromo-7-chloroimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate(216 mg, 0.56 mmol) in ethanol (3 mL), THF (3 mL) and H₂O (1.5 mL) wasadded LiOH.H₂O (95 mg, 2.25 mmol). The mixture was stirred at 65° C. for3 h. Most of the solvent was concentrated and the residue was adjustedto pH to 4 by adding 1 M HCl solution. The resulting precipitate wasfiltered to give1-((6-bromo-7-chloroimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylicacid (190 mg, yield: 95%) as a white solid. ESI-MS [M+H]⁺: 355.0.

Synthesis of1-((6-bromo-7-chloroimidazo[1,2-a]pyridin-2-yl)methyl)-N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide(I-36)

A mixture of1-((6-bromo-7-chloroimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylicacid (95 mg, 0.27 mmol), (7-chloroimidazo[1,5-a]pyridin-1-yl)methanamine(55 mg, 0.25 mmol), HATU (190 mg, 0.5 mmol) and DIPEA (97 mg, 0.75 mmol)in DMF (4 mL) was stirred at RT for 3 h. Water (30 mL) was added andextracted with ethyl acetate (3×30 mL). The combined organic layers wereconcentrated and purified by prep-TLC (DCM:MeOH=8:1) to give1-((6-bromo-7-chloroimidazo[1,2-a]pyridin-2-yl)methyl)-N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide(49.2 mg, yield: 38%) as a white solid. ESI-MS [M+H]⁺: 517.9. Purity:96.34%. ¹H NMR (400 MHz, DMSO): δ 9.06 (s, 1H), 8.58 (s, 1H), 8.30-8.22(m, 3H), 7.92-7.77 (m, 4H), 6.64 (s, 1H), 5.42 (s, 2H), 4.54 (s, 2H).

Example 37

Synthesis of1-((6-bromo-7-chloroimidazo[1,2-a]pyridin-2-yl)methyl)-N-((7-bromoimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide(I-37)

A mixture of1-((6-bromo-7-chloroimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylicacid (95 mg, 0.27 mmol), (7-bromoimidazo[1,5-a]pyridin-1-yl)methanamine(56 mg, 0.25 mmol), HATU (190 mg, 0.5 mmol) and DIPEA (97 mg, 0.75 mmol)in DMF (4 mL) was stirred at RT for 3 h. Water (30 mL) was added and themixture was extracted with ethyl acetate (3×30 mL). The combined organiclayers were concentrated and purified by prep-TLC (DCM:MeOH=8:1) to give1-((6-bromo-7-chloroimidazo[1,2-a]pyridin-2-yl)methyl)-N-((7-bromoimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide(43.3 mg, yield: 31%) as a white solid. ESI-MS [M+H]⁺: 561.9. Purity:90%. 1H NMR (400 MHz, DMSO): δ 9.06 (s, 1H), 8.58 (t, J=4.9 Hz, 1H),8.31 (s, 1H), 8.23-8.22 (m, 2H), 7.94-7.93 (m, 2H), 7.86 (s, 1H), 7.80(s, 1H), 6.71 (d, J=7.3 Hz, 1H), 5.43 (s, 2H), 4.54 (d, J=5.3 Hz, 2H).

Example 38

Synthesis of Ethyl 2-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)acetate

A mixture of 5-cyclopropylpyridin-2-amine (3 g, 22.4 mmol) and ethyl4-chloro-3-oxobutanoate (11 g, 67.2 mmol) in EtOH (150 mL) was stirredat 90° C. for 15 h. The pH of the reaction was adjusted to 8-9 withNaHCO₃ (4 M, 50 mL) and extracted with EtOAc (70 mL×3). The combinedorganic layers were washed with brine, dried over Na₂SO₄ andconcentrated to give the crude, which was purified by silica gelchromatography (EA/PE=1/1) to give ethyl2-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)acetate (3.6 g, yield: 72%)as a black solid. ESI-MS [M+H]⁺: 225.2.

Synthesis of 2-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)acetamide

A solution of ethyl 2-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)acetate(3.6 g, 16 mmol) in NH₃ (7 M solution in MeOH, 50 mL) in sealed tube wasstirred at 60° C. for 12 h. The reaction was concentrated to give the2-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)acetamide, which was used inthe next step without further purification (3.4 g, yield: 99%) as ayellow oil. ESI-MS [M+H]⁺: 216.2.

Synthesis of 2-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)ethanethioamide

To a solution of 2-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)acetamide(3.4 g, 15.8 mmol) in dioxane (50 mL) was added Lawesson's reagent (6.3g, 15.8 mmol) at 0° C. The resulting mixture was stirred at RT for 6 h.The reaction was quenched with H₂O (70 mL) and extracted with EtOAc (50mL×3). The combined organic layers were washed with brine, dried overNa₂SO₄, filtered and concentrated to give the2-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)ethanethioamide which wasused in the next step without further purification. (3 g, yield: 82%) asa yellow oil. ESI-MS [M+H]⁺: 232.2.

Synthesis of Ethyl2-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)thiazole-5-carboxylate

A mixture of 2-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)ethanethioamide(700 mg, 3.1 mmol), pyridine (480 mg, 6.2 mmol) and ethyl2-chloro-3-oxopropanoate (678 mg, 4.65 mmol) in EtOH (25 mL) was stirredat 65° C. for 14 h. The reaction was concentrated to give the crude,which was purified with silica gel chromatography (EA/PE=1/1) to givethe ethyl2-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)thiazole-5-carboxylate(105 mg, yield: 10.7%) as a yellow solid. ESI-MS [M+H]⁺: 327.1.

Synthesis of2-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)thiazole-5-carboxylicAcid

A mixture of ethyl2-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)thiazole-5-carboxylate(105 mg, 0.32 mmol) and LiOH (23 mg, 0.96 mmol) in THF/EtOH/H₂O (2 mL/2mL/1 mL) was stirred at 80° C. for 2 h. The pH value of the reaction wasadjusted to 4 by adding 1 M HCl solution, and then concentrated to givethe crude, which was used in the next step without further purification(105 mg, crude yield: 100%). ESI-MS [M+H]⁺: 300.2.

Synthesis ofN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-2-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)thiazole-5-carboxamide(I-38)

To a solution of2-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)thiazole-5-carboxylicacid (105 mg, crude from last step) in DMF (5 mL) was added HATU (160mg, 0.42 mmol) and DIPEA (226 mg, 1.75 mmol). The mixture reaction wasstirred for 30 min, then (7-chloroimidazo[1,5-a]pyridin-1-yl)methanaminehydrochloride (99 mg, 0.45 mmol) was added. The resulting mixture wasstirred at RT for 12 h. Water (25 mL) was added and the mixture wasextracted with EtOAc (30 mL×3). The combined organic layers were washedwith brine, dried over Na₂SO₄, concentrated to give the crude, which waspurified with prep-TLC (DCM/MeOH=10/1) to give theN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-2-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)thiazole-5-carboxamideas a white solid (15 mg, yield: 9.3%). ESI-MS [M+H]⁺: 463.1. Purity:98.5%. ¹H NMR (400 MHz, MeOD): δ 8.30-8.27 (m, 2H), 8.19-8.16 (m, 2H),7.81 (s, 1H), 7.73 (s, 1H), 7.49 (d, J=9.4 Hz, 1H), 7.30 (dd, J=9.4, 1.5Hz, 1H), 6.63 (dd, J=7.5, 2.0 Hz, 1H), 4.70 (s, 2H), 4.53 (s, 2H),1.99-1.97 (m, 1H), 1.11-1.00 (m, 2H), 0.77-0.74 (m, 2H).

Example 39

Synthesis of 6-bromo-5-chloro-2-(chloromethyl)imidazo[1,2-a]pyridine

The mixture of 5-bromo-6-chloropyridin-2-amine (1.38 g, 6.65 mmol) and1,3-dichloropropan-2-one (3.35 g, 26.61 mmol) in DMF (20 mL) was stirredat 95° C. for 4 h. The reaction mixture was quenched with H₂O (150 mL)followed by adding saturated NaHCO₃ (20 mL) solution, the mixture wasthen extracted with EtOAc (100 mL×2). The combined organic layers werewashed with brine (150 mL×2), dried over Na₂SO₄, concentrated andpurified by trituration with EtOAc to give6-bromo-5-chloro-2-(chloromethyl)imidazo[1,2-a]pyridine (480 mg, 26%) asa light brown solid. ESI-MS [M+H]⁺: 279.0.

Synthesis of Ethyl1-((6-bromo-5-chloroimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate

The mixture of 6-bromo-5-chloro-2-(chloromethyl)imidazo[1,2-a]pyridine(380 mg, 1.36 mmol), ethyl 1H-pyrazole-4-carboxylate (190 mg, 1.36 mmol)and CsCO₃ (663 mg, 2.04 mmol) in DMF (10 mL) was stirred for at 50° C.for 4 h. The reaction mixture was diluted with H₂O (80 mL) and extractedwith EtOAc (100 mL×3). The combined organic layers were washed withbrine, dried over Na₂SO₄, concentrated and purified by silica gelchromatography (EA/PE=1/4) to give ethyl1-((6-bromo-5-chloroimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate(400 mg, yield: 77%) as a yellow solid. ESI-MS [M+H]⁺: 383.0.

Synthesis of1-((6-bromo-5-chloroimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylicAcid

A mixture of ethyl1-((6-bromo-5-chloroimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate(350 mg, 0.912 mmol) and LiOH.H₂O (307 mg, 7.30 mmol) in THF (10 mL) andH₂O (2 mL) was stirred at 40° C. for 16 h. Most of the solvent wasremoved and the residue was diluted with H₂O (10 mL). The pH value ofmixture was adjusted to 4-5 by adding HCl (1 M). The precipitate wascollected and dried to give1-((6-bromo-5-chloroimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylicacid (285 mg, yield: 88%) as a white solid. ESI-MS [M+H]⁺: 354.9.

Synthesis of1-((6-bromo-5-chloroimidazo[1,2-a]pyridin-2-yl)methyl)-N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide(I-39)

The mixture of1-((6-bromo-5-chloroimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylicacid (80 mg, 0.22 mmol), HATU (92 mg, 0.242 mmol) and DIPEA (85 mg, 0.66mmol) in DMF (3 mL) was stirred at RT for 10 min.(7-chloroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride (48 mg,0.22 mmol) was added and stirred at RT for 1 h. The reaction mixture wasquenched with H₂O (50 mL) and extracted with EtOAc/THF (40 mL×3, 5/1(v/v)). The combined organic layers was washed with brine (100 mL×3),dried over Na₂SO₄, concentrated and purified by prep-TLC (DCM/MeOH=7/1)to give1-((6-bromo-5-chloroimidazo[1,2-a]pyridin-2-yl)methyl)-N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide(50 mg, yield: 43%) as a yellow solid. ESI-MS [M+H]⁺: 518.0. Purity:99.23%. ¹H NMR (400 MHz, DMSO): δ 8.59 (t, J=5.7 Hz, 1H), 8.33-8.28 (m,2H), 8.25 (s, 1H), 8.02 (s, 1H), 7.87 (s, 1H), 7.78-7.77 (m, 1H),7.62-7.55 (m, 2H), 6.66-6.63 (m, 1H), 5.47 (s, 2H), 4.55 (d, J=5.7 Hz,2H).

Example 40

Synthesis of1-((6-bromo-5-chloroimidazo[1,2-a]pyridin-2-yl)methyl)-N-((7-bromoimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide(I-40)

The mixture of1-((6-bromo-5-chloroimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylicacid (70 mg, 0.20 mmol), HATU (82 mg, 0.217 mmol) and DIPEA (76 mg,0.591 mmol) in DMF (3 mL) was stirred at RT for 10 min.(7-bromoimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride (52 mg,0.20 mmol) was added and stirred at RT for 1 h. The reaction mixture wasdiluted with H₂O (50 mL) and extracted with EtOAc/THF (40 mL×3, 5/1(v/v)). The combined organic layers were washed with brine (100 mL×3),dried over Na₂SO₄, concentrated and purified by prep-TLC (DCM/MeOH=7/1)to give1-((6-bromo-5-chloroimidazo[1,2-a]pyridin-2-yl)methyl)-N-((7-bromoimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide(40 mg, yield: 36%) as a yellow solid. ESI-MS [M+H]⁺: 561.9. Purity:92.54%. ¹H NMR (400 MHz, DMSO): δ 8.58 (t, J=5.5 Hz, 1H), 8.32 (s, 1H),8.26-8.22 (m, 2H), 8.02 (s, 1H), 7.95 (s, 1H), 7.87 (s, 1H), 7.61-7.55(m, 2H), 6.72 (d, J=8.9 Hz, 1H), 5.47 (s, 2H), 4.55 (d, J=5.6 Hz, 2H).

Example 41

Synthesis of Ethyl1-((7-(2,2-dimethylcyclopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate

A mixture of ethyl1-((7-bromoimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate(120 mg, 0.34 mmol),2-(2,2-dimethylcyclopropyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(0.33 g, 1.7 mmol), Pd(OAc)₂ (8 mg, 0.034), PCy₃ (10 mg, 0.034 mmol),and K₃PO₄ (220 mg, 1.3 mmol) in 1,4-dioxane (3 mL) and H₂O (1 mL) wasstirred at 100° C. under microwave for 7 h. The reaction was filteredthrough celite and washed with DCM/MeOH (10/1, 30 mL). The filtrate wasconcentrated and purified by silica gel (DCM/MeOH=10/1) to give the1-((7-(2,2-dimethylcyclopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate(60 mg, 70%) as a yellow solid. ESI-MS [M+H]⁺: 339.1.

Synthesis of Ethyl1-((7-(2,2-dimethylcyclopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate

A mixture of1-((7-(2,2-dimethylcyclopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate(61 mg, 0.18 mmol) and LiOH (27.6 mg, 1.2 mmol) in THF/EtOH/H₂O (3 mL/3mL/2 mL) was stirred at 80° C. for 2 h. The pH value of the reaction wasadjusted to around 5 and a yellow solid precipitated out. The solid wasfiltered and the filter cake was dried to give1-((7-(2,2-dimethylcyclopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate(50 mg, yield: 89%) as a yellow solid. ESI-MS [M+H]⁺: 311.1.

Synthesis ofN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((7-(2,2-dimethylcyclopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(I-41)

To a solution of1-((7-(2,2-dimethylcyclopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate(55 mg, 0.18 mmol), (7-chloroimidazo[1,5-a]pyridin-1-yl)methanamine (38mg, 0.21 mmol) and HATU (101 mg, 0.27 mmol) in DMF (15 mL) was addedDIPEA (187 mg, 1.55 mmol). The resulting reaction stirred at RT for 2 h.H₂O (30 mL) was added to the reaction and extracted with EtOAc (30mL×3). The combined organic layers were washed with brine, dried overNa₂SO₄, concentrated in vacuo to give the crude, which was purified withprep-TLC (DCM/MeOH=10/1) to give theN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((7-(2,2-dimethylcyclopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(12.3 mg, yield: 10%) as a white solid. ESI-MS [M+H]⁺: 474.1. Purity:94.0%. ¹H NMR (400 MHz, MeOD): δ 8.27 (d, J=2.7 Hz, 2H), 8.20-8.15 (m,2H), 7.93 (s, 1H), 7.85 (s, 1H), 7.74 (m, 1H), 7.52-7.47 (m, 2H),6.68-6.60 (m, 1H), 5.52 (s, 2H), 4.69 (s, 2H), 1.95-1.88 (m, 1H), 1.26(s, 3H), 0.89 (s, 1H), 0.88 (d, J=2.5 Hz, 1H), 0.83 (s, 3H).

Synthesis of2-(2,2-dimethylcyclopropyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

To a solution of4,4,5,5-tetramethyl-2-(2-methylprop-1-en-1-yl)-1,3,2-dioxaborolane (100mg, 0.55 mmol) in toluene (5 mL) was added CH₂I₂ (0.42 g, 1.54 mmol)dropwise at 0° C. The resulting reaction was stirred at 55° C.overnight. The reaction was filtered and washed with DCM (10 mL). Thecrude product was extracted with H₂O (10 mL), dried over Na₂SO₄,concentrated to give the2-(2,2-dimethylcyclopropyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (200mg crude) which was used in the next step without further purification.ESI-MS [M+H]⁺: 197.1.

Example 42

Synthesis of Ethyl1-((7-(2-methylprop-1-en-1-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate

A solution of ethyl1-((7-bromoimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate(200 mg, 0.57 mmol),4,4,5,5-tetramethyl-2-(2-methylprop-1-en-1-yl)-1,3,2-dioxaborolane (207mg, 1.14 mmol), Pd(dppf)Cl₂ (42, 0.057 mg), and K₃PO₄ (364 mg, 1.72mmol) in 1,4-dioxane (10 mL) and H₂O (1 mL) in a sealed tube was stirredat 100° C. under microwave for 3 h. The reaction was filtered throughcelite and washed with EtOAc. The filtrate was concentrated and purifiedby silica gel (PE/EA=1:2) to give the1-((7-(2-methylprop-1-en-1-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate(200 mg, 90%) as a brown solid. ESI-MS [M+H]⁺: 325.1.

Synthesis of1-((7-(2-methylprop-1-en-1-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylicAcid

A mixture of1-((7-(2-methylprop-1-en-1-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate(60 mg, 0.18 mmol) and LiOH (27 mg, 1.2 mmol) in THF/EtOH/H₂O (3 mL/3mL/2 mL) was stirred at 80° C. for 2 h. The pH value of reaction wasadjusted to around 5 by adding 1 M HCl solution and a solid wasprecipitated. The solid was filtered and the filter cake was dried togive1-((7-(2-methylprop-1-en-1-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylicacid (50 mg, yield: 89%) as a brown solid. ESI-MS [M+H]⁺: 297.1.

Synthesis ofN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((7-(2-methylprop-1-en-1-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(I-42)

To a solution of1-((7-(2-methylprop-1-en-1-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylicacid (53 mg, 0.18 mmol), (7-chloroimidazo[1,5-a]pyridin-1-yl)methanamine(38 mg, 0.21 mmol) and HATU (101 mg, 0.27 mmol) in DMF (15 mL) was addedDIPEA (200 mg, 1.55 mmol). The resulting reaction stirred at RT for 2 h.H₂O (30 mL) was added and the reaction mixture was extracted with EtOAc(30 mL×3). The combined organic layers were washed with brine, driedover Na₂SO₄, concentrated in vacuo to give the crude, which was purifiedby prep-TLC (DCM/MeOH=10/1) to give theN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((7-(2-methylprop-1-en-1-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(30 mg, yield: 36%) as a white solid. ESI-MS [M+H]⁺: 460.1. Purity:95.2%. ¹H NMR (400 MHz, MeOD): δ 8.35 (s, 1H), 8.28 (s, 1H), 8.18-8.46(m, 2H), 7.94 (s, 1H), 7.90 (s, 1H), 7.74 (s, 1H), 7.54 (d, J=9.3 Hz,1H), 7.49-7.38 (m, 1H), 6.63 (dd, J=7.5, 1.9 Hz, 1H), 6.22 (s, 1H), 5.54(s, 2H), 4.69 (s, 2H), 1.95 (s, 3H), 1.88 (s, 3H).

Example 43

Synthesis of tert-butyl (Z)-(5-(prop-1-en-1-yl)pyridin-2-yl)carbamate

To a mixture of tert-butyl (5-bromopyridin-2-yl)carbamate (2.73 g, 10mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (3.81g, 15 mmol) and KOAc (3.0 g, 30 mmol) in dioxane (30 mL) was addedPd(dppf)Cl₂ (881 mg, 1 mmol). The mixture was stirred at 100° C. for 16h. After cooling, (Z)-1-bromoprop-1-ene (3.6 g, 30 mmol), Cs₂CO₃ (6.4 g,20 mmol) and Pd(PPh₃)₄ (500 mg, 0.5 mmol) were added. The mixture wasstirred 100° C. for another 16 h. Water (100 mL) was added and themixture was extracted with EtOAc (100 mL×3). The combined organic layerswere concentrated and purified by silica gel chromatography (EA/PE=1/2)to give tert-butyl (Z)-(5-(prop-1-en-1-yl)pyridin-2-yl)carbamate (230mg, yield: 10%) as a white solid. ESI-MS [M+H]⁺: 235.1.

Synthesis of 5-(2-methylcyclopropyl)pyridin-2-amine

To a solution of ZnEt₂ (1 M, 10 mmL) in DCM (20 mL) was added TFA (1.14g, 10 mmol), followed by CH₂I₂ (2.68 g, 10 mmol). After the resultingmixture was stirred at 0° C. for 10 min, tert-butyl(Z)-(5-(prop-1-en-1-yl)pyridin-2-yl)carbamate (230 mg, 1.0 mmol) wasadded. The mixture was stirred at RT for 3 h. Water (50 mL) was addedand extracted with EtOAc (100 mL×3). The combined organic layers wereconcentrated and purified by prep-HPLC to give5-(2-methylcyclopropyl)pyridin-2-amine (60 mg, yield: 12%) as a yellowoil. ESI-MS [M+H]⁺: 149.1.

Synthesis of2-(chloromethyl)-6-(2-methylcyclopropyl)imidazo[1,2-a]pyridine

To a solution of 5-(2-methylcyclopropyl)pyridin-2-amine (600 mg, 0.4mmol) in DMF (5 mL) was added 1,3-dichloropropan-2-one (206 mg, 1.6mmol). The mixture was stirred at 90° C. for 2 h. Water (50 mL) wasadded and extracted with EtOAc (50 mL×3). The combined organic layerswere washed with brine, dried over Na₂SO₄, filtered and concentrated togive the crude, which was purified by silica gel chromatography(EA/PE=1/1) to give2-(chloromethyl)-6-(2-methylcyclopropyl)imidazo[1,2-a]pyridine (40 mg,yield: 79%) as a yellow oil. ESI-MS [M+H]⁺: 221.1.

Synthesis of Ethyl1-((6-(2-methylcyclopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate

To a solution of2-(chloromethyl)-6-(2-methylcyclopropyl)imidazo[1,2-a]pyridine (40 mg,0.18 mmol) and ethyl 1H-pyrazole-4-carboxylate (30 mg, 0.22 mmol) in DMF(3 mL) was added CsCO₃ (118 mg, 0.36 mmol) at RT. The mixture wasstirred at RT for 2 h. The reaction was diluted with H₂O (30 mL) andextracted with ethyl acetate (3×50 mL). The combined organic layers werewashed with brine, dried over sodium sulfate, concentrated and purifiedby prep-TLC (MeOH/DCM=1/10) to give ethyl1-((6-(2-methylcyclopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate(30 mg, yield: 50%) as a yellow oil. ESI-MS [M+H]⁺: 325.1.

Synthesis of1-((6-(2-methylcyclopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylicAcid

To a solution of ethyl1-((6-((1S,2R)-2-methylcyclopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate(30 mg, 0.1 mmol) in a mixed solvent of THF/EtOH/H₂O (2 mL/2 mL/1 mL)was added NaOH (4 M, 0.1 mL, 0.4 mmol). The mixture was stirred atrefluxed for 3 h. Most of the solvent was removed and the residue wasdiluted with H₂O (3 mL) and the pH value of mixture was adjusted to 4-5by adding HCl aqueous (1 M). The mixture was freeze-dried to give1-((6-(2-methylcyclopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylicacid (crude, 40 mg) as a yellow solid which was used in the next stepwithout purification. ESI-MS [M+H]⁺: 297.1.

Synthesis ofN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-(2-methylcyclopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(I-43)

To a solution of1-((6-(2-methylcyclopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylicacid (40 mg, crude from last step) and(7-chloroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride (44 mg,0.2 mmol) in dry DMF (1 mL) was added HATU (106 mg, 0.28 mmol) and DIPEA(90 mg, 0.7 mmol) at RT. The reaction was stirred at RT for 3 h. Water(20 mL) was added and the mixture was extracted with EtOAc (30 mL×3).The combined organic layers were washed with brine (5 mL), dried oversodium sulfate, concentrated and purified by prep-TLC (DCM/MeOH=10/1) togiveN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-(2-methylcyclopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-3-carboxamide(25 mg, yield: 54% for two steps) as a yellow solid. ESI-MS [M+H]⁺:460.1. Purity: 91%. ¹H NMR (400 MHz, DMSO): δ 8.58 (t, J=5.3 Hz, 1H),8.31-8.29 (m, 3H), 8.23 (s, 1H), 7.86 (s, 1H), 7.78 (s, 1H), 7.73 (s,1H), 7.40 (d, J=9.0 Hz, 1H), 7.14 (d, J=8.9 Hz, 1H), 6.64 (dd, J=7.5,1.9 Hz, 1H), 5.39 (s, 2H), 4.55 (d, J=5.7 Hz, 2H), 2.02 (dd, J=14.3, 8.6Hz, 1H), 1.18-1.07 (m, 1H), 1.04-0.88 (m, 1H), 0.75 (d, J=6.2 Hz, 3H),0.60 (dd, J=10.5, 5.2 Hz, 1H).

Example 44

Synthesis ofN-((7-bromoimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-(2-methylcyclopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(I-44)

To a solution of1-((6-(2-methylcyclopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylicacid (40 mg, 0.1 mmol) and(7-bromoimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride (52 mg, 0.2mmol) in dry DMF (3 mL) was added HATU (106 mg, 0.28 mmol) and DIPEA (90mg, 0.7 mmol) at RT. The reaction was stirred at RT for 3 h. Water (20mL) was added and the mixture was extracted with EtOAc (30 mL×3). Thecombined organic layers were washed with brine (50 mL), dried oversodium sulfate, concentrated and purified by prep-TLC (DCM/MeOH=10/1) togiveN-((7-bromoimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-(2-methylcyclopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(25.5 mg, yield: 37%) as a yellow solid. ESI-MS [M+H]⁺: 504.1. Purity:91.53%. ¹H NMR (400 MHz, DMSO): δ 8.59 (t, J=5.7 Hz, 1H), 8.31 (s, 2H),8.26-8.19 (m, 2H), 8.00-7.92 (m, 1H), 7.86 (s, 1H), 7.73 (s, 1H), 7.40(d, J=9.3 Hz, 1H), 7.15 (dd, J=9.3, 1.6 Hz, 1H), 6.72 (dd, J=7.4, 1.9Hz, 1H), 5.39 (s, 2H), 4.55 (d, J=5.7 Hz, 2H), 2.02 (dd, J=14.4, 8.4 Hz,1H), 1.18-1.11 (m, 1H), 0.99-0.93 (m, 1H), 0.75 (d, J=6.2 Hz, 3H), 0.60(dd, J=10.7, 5.5 Hz, 1H).

Example 45

Synthesis of1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-((7-iodoimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide(I-45)

To a solution of1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylicacid (60 mg, 0.21 mmol), (7-iodoimidazo[1,5-a]pyridin-1-yl)methanaminehydrochloride (99 mg, 0.32 mmol) and HATU (120 mg, 0.31 mmol) in DMF (5mL) was added DIPEA (81 mg, 0.63 mmol). The resulting reaction wasstirred at RT for 12 h. H₂O (25 mL) was added to the reaction, extractedwith EtOAc (50 mL×3). The combined organic layers were washed withbrine, dried over Na₂SO₄ and concentrated in vacuo to give the crude,which was purified with prep-TLC (DCM/MeOH=10/1) to give the1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-((7-iodoimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide(20 mg, yield: 18%) as a white solid. ESI-MS [M+H]⁺: 538.0. Purity:97.4%. ¹H NMR (400 MHz, DMSO): δ 8.56 (t, J=5.7 Hz, 1H), 8.32 (s, 1H),8.29 (s, 1H), 8.20 (s, 1H), 8.13 (s, 1H), 8.12-8.08 (m, 1H), 7.85 (s,1H), 7.71 (s, 1H), 7.39 (d, J=9.3 Hz, 1H), 6.99 (dd, J=9.3, 1.7 Hz, 1H),6.78 (dd, J=7.3, 1.6 Hz, 1H), 5.39 (s, 2H), 4.54 (d, J=5.7 Hz, 2H),1.94-1.88 (m, 1H), 0.96-0.85 (m, 2H), 0.71-0.58 (m, 2H).

Example 46

Synthesis of 2-(chloromethyl)-5-ethylimidazo[1,2-a]pyridine

A solution of 6-ethylpyridin-2-amine (1 g, 8.2 mmol) and 1,3-dichloropropan-2-one (4.7 g, 36.9 mmol) in DMF (10 mL) was stirred at90° C. for 3 h. Then the reaction mixture was diluted with H₂O (100 mL)and extracted with EtOAc (100 mL×3). The combined organic layers weredried over Na₂SO₄, concentrated and purified by column chromatography(CH₂Cl₂:MeOH=20:1) to give the desired product2-(chloromethyl)-5-ethylimidazo[1,2-a]pyridine (450 mg, yield: 28%) as awhite solid. ESI-MS [M+H]⁺: 195.1.

Synthesis ofN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((5-ethylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(I-46)

A solution of 2-(chloromethyl)-5-ethylimidazo[1,2-a]pyridine (60 mg,0.31 mmol),N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamideand Cs₂CO₃ (303 mg, 0.93 mmol) in DMF (3 mL) was stirred at RT for 2 h.Then the reaction mixture was diluted with H₂O (50 mL) and extractedwith EtOAc (50 mL×3). The combined organic layers were dried overNa₂SO₄, concentrated and purified by column chromatography(CH₂Cl₂I/MeOH=20/1) to give the desired compoundN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((5-ethylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(16 mg, yield: 12%) as a white solid. ESI-MS [M+H]⁺: 434.1. Purity:98.90%. ¹H NMR (400 MHz, DMSO): δ 8.58 (t, J=5.8 Hz, 2H), 8.33-8.27 (m,2H), 8.23 (s, 1H), 7.86 (d, J=6.8 Hz, 2H), 7.80-7.75 (m, 1H), 7.42 (d,J=9.0 Hz, 1H), 7.29-7.21 (m, 1H), 6.78-6.73 (m, 1H), 6.67-6.61 (m, 1H),5.42 (s, 2H), 4.55 (d, J=5.8 Hz, 2H), 2.95-2.86 m, 2H), 1.36-1.27 (m,3H).

Example 47

Synthesis of(Z)-1-((6-(prop-1-en-1-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylicAcid

A mixture of ethyl(Z)-1-((6-(prop-1-en-1-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate(150 mg, 0.48 mmol) and NaOH (40 mg, 1.6 mmol) in EtOH/H2O (2 mL/1 mL)was stirred at 50° C. for 3 h. The reaction was monitored by LCMS untilthe starting material consumed. The pH value of mixture was adjusted to2-3 by adding 1 M aqueous HCl solution and extracted with EtOAc (50mL×3). The combined organic layers were concentrated to give(Z)-1-((6-(prop-1-en-1-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylicacid (65 mg, 48% yield) as a white solid. ESI-MS [M+H]⁺: 283.0.

Synthesis of(Z)—N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-(prop-1-en-1-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(I-47)

A mixture of1-((6-methylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylicacid (65 mg, 0.23 mmol) in DMF (3 mL) was added(5-chloro-2H-indazol-3-yl)methanamine hydrochloride (100 mg, 0.46 mmol),DIPEA (150 mg, 1.15 mmol) and HATU (133 mg, 0.35 mmol). The resultingmixture was stirred at RT for 3 h. The reaction was quenched with H₂O(30 mL) and extracted with EtOAc (30 mL×3). The combined organic layerswere washed with brine, dried over Na₂SO₄, concentrated in vacuo to givethe crude, which was purified with prep-TLC (EA/PE=1/5) to give the(Z)—N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-(prop-1-en-1-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(9.3 mg, yield: 6.2%) as a white solid. ESI-MS [M+H]⁺: 446.1. Purity:95.3%. ¹H NMR (400 MHz, DMSO): δ 8.60 (t, J=5.6 Hz, 1H), 8.50 (s, 1H),8.38-8.26 (m, 2H), 8.24 (s, 1H), 7.87 (s, 1H), 7.80 (d, J=14.2 Hz, 2H),7.48 (d, J=9.3 Hz, 1H), 7.22 (d, J=9.3 Hz, 1H), 6.65 (dd, J=7.4, 2.0 Hz,1H), 6.35 (d, J=11.5 Hz, 1H), 5.84 (td, J=14.4, 7.1 Hz, 1H), 5.42 (s,2H), 4.56 (d, J=5.7 Hz, 2H), 1.87 (dd, J=7.2, 1.6 Hz, 3H).

Example 48

Synthesis of 5-cyclopropylpyridin-2-amine

A solution of 5-bromopyridin-2-amine (5 g, 29.1 mmol),cyclopropylboronic acid (3.75 g, 43.6 mmol), Pd(OAc)₂ (651 mg, 2.91mmol), SPhos (1.19 g, 2.91 mmol) and K₃PO₄ (18.5 g, 87.3 mmol) intoluene/H₂O (100 mL/10 mL) was stirred at 95° C. for 12 h undernitrogen. Then the reaction mixture was quenched with H₂O (50 mL) andextracted with DCM (200 mL). The combined organic layers were dried overNa₂SO₄ and concentrated in vacuo to give the crude residue which waspurified by silica gel chromatography (PE/EtOAc=1/1) to give the5-cyclopropylpyridin-2-amine as yellow solid (3.8 g, 97.4% yield).ESI-MS [M+H]⁺: 135.2.

Synthesis of 2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine

To a solution 5-cyclopropyl-4-methylpyridin-2-amine (500 mg, 3.70 mmol)in DMF (10 mL) was added 1,3-dichloropropan-2-one (1409 mg, 11.1 mmol)at RT. The resulting reaction was stirred at 85° C. for 2 h. Thesolution was quenched with H₂O (60 mL), adjusted to pH 8 by addingsaturated NaHCO₃ solution, and extracted with EtOAc (50 mL×3). Thecombined organic layers were washed with brine, dried over Na₂SO₄, andconcentrated in vacuo to give the crude, which was purified withprep-TLC (PE/EtOAc=1/1) to give the2-(chloromethyl)-6-cyclopropyl-7-methylimidazo[1,2-a]pyridine (300 mg,yield: 39%) as a light yellow oil. ESI-MS [M+H]⁺: 207.2.

Synthesis of Ethyl1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate

To a solution 2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine (2 g,9.70 mmol) in DMF (20 mL) was added ethyl 1H-pyrazole-4-carboxylate (906mg, 6.46 mmol) and Cs₂CO₃ (6.32 g, 19.38 mmol) at RT. The resultingreaction was stirred at RT for 12 h. H₂O (150 mL) was added to thereaction and then the mixture was extracted with EtOAc (100 mL×3). Thecombined organic layers were washed with brine, dried over Na₂SO₄,concentrated in vacuo to give the crude, which was purified with silicagel chromatography (DCM/MeOH=20/1) to give the ethyl1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate(1.5 g, yield: 75%) as a white solid. ESI-MS [M+H]⁺: 311.2.

Synthesis of1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylicAcid

To a solution of ethyl 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate (1.2 g, 3.87 mmol) in THF (20 mL) andH₂O (10 mL) was added LiOH (464 mg, 19.35 mmol). The mixture was stirredat RT for 16 h. Most of the THF was removed and the pH was adjusted to4-5 by adding HCl (1 M). The resulting precipitate was collected anddried to give the 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylic acid as a whitesolid (1.0 g, yield: 91%). ESI-MS [M+H]⁺: 283.2.

Synthesis of1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-((7-cyclopropylimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide(I-48)

To a solution of1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylicacid (60 mg, 0.21 mmol),(7-cyclopropylimidazo[1,5-a]pyridin-1-yl)methanamine (59 mg, 0.32 mmol)and HATU (120 mg, 0.31 mmol) in DMF (5 mL) was added DIPEA (81 mg, 0.63mmol). The resulting reaction was stirred at RT for 12 h. H₂O (30 mL)was added to the reaction, extracted with EtOAc (50 mL×3). The combinedorganic layers were washed with brine, dried over Na₂SO₄ andconcentrated in vacuo to give the crude, which was purified withprep-TLC (DCM/MeOH=10/1) to give the 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-((7-cyclopropylimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide(20 mg, yield: 21%) as a white solid. ESI-MS [M+H]⁺: 452.2. Purity:99.8%. ¹H NMR (400 MHz, DMSO): δ 8.47 (t, J=5.6 Hz, 1H), 8.32 (s, 1H),8.21 (s, 1H), 8.16-8.14 (m, 2H), 7.86 (s, 1H), 7.71 (s, 1H), 7.40-7.38(m, 1H), 7.32 (s, 1H), 7.00-6.97 (m, 1H), 6.32-6.30 (m, 1H), 5.38 (s,2H), 4.55 (d, J=5.6 Hz, 2H), 1.95-1.78 (m, 2H), 0.95-0.83 (m, 4H),0.70-0.60 (m, 4H).

Example 49

Synthesis ofN-((7-bromoimidazo[1,5-a]pyridin-1-yl)methyl)-1-((7-(2,2-dimethylcyclopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(I-49)

To a solution of1-((7-(2,2-dimethylcyclopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate(56 mg, 0.18 mmol), (7-bromoimidazo[1,5-a]pyridin-1-yl)methanaminehydrochloride (55 mg, 0.21 mmol) and HATU (102 mg, 0.27 mmol) in DMF (10mL) was added DIPEA (199 mg, 1.55 mmol). The resulting reaction stirredat RT for 2 h. H₂O (30 mL) was added to the reaction and extracted withEtOAc (30 mL×3). The combined organic layers were washed with brine,dried over Na₂SO₄ and concentrated in vacuo to give the crude, which waspurified with prep-TLC (DCM/MeOH=10/1) to give theN-((7-bromoimidazo[1,5-a]pyridin-1-yl)methyl)-1-((7-(2,2-dimethylcyclopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(17.5 mg, yield: 18.8%) as a white solid. ESI-MS [M+H]⁺: 518.1. Purity:91.25%. H NMR (400 MHz, MeOD): δ 8.85 (s, 1H), 8.53 (s, 1H), 8.30 (s,1H), 8.24 (d, J=7.5 Hz, 1H), 8.11 (s, 2H), 7.98 (s, 1H), 7.87 (dd,J=9.3, 1.4 Hz, 1H), 7.75 (d, J=9.3 Hz, 1H), 6.98 (dd, J=7.5, 1.4 Hz,1H), 5.68 (s, 2H), 4.77 (s, 2H), 2.03-1.98 (m, 1H), 1.29 (s, 3H),1.00-0.93 (m, 2H), 0.85 (s, 3H).

Example 50

Synthesis of 4-cyclopropylpyridine

A mixture of 4-bromopyridine (5 g, 25.71 mmol), cyclopropylboronic acid(2.5 g, 28.28 mmol), K₂CO₃ (10.6 g, 77.13 mmol) and Pd(dppf)₂Cl₂ (2.1 g,2.57 mmol) in dioxane (80 mL) and H₂O (16 mL) was refluxed under N₂ for16 h. The reaction mixture was filtered through celite and washed withEtOAc (20 mL). The solvent was evaporated, the residue was diluted withH₂O (30 mL) and extracted with EtOAc (50 mL×3). The combined organiclayers were dried over Na₂SO₄, filtered and concentrated to give ayellow oil, which was purified by silica gel chromatography to give4-cyclopropylpyridine (2.774 g, yield: 91.5%) as a yellow oil. ESI-MS[M+H]⁺: 120.1.

Synthesis of 1-amino-4-cyclopropylpyridin-1-ium2,4,6-trimethylbenzenesulfonate

To a solution of 4-cyclopropylpyridine (1.5 g, 12.61 mmol) in DCM (5 mL)was added O-(mesitylsulfonyl)hydroxylamine (2.7 g, 12.61 mmol) at 0° C.,then the reaction mixture was stirred at RT for 2 h. The reactionmixture was concentrated to give the 1-amino-4-cyclopropylpyridin-1-ium2,4,6-trimethylbenzenesulfonate (4.2 g, yield: 100%) as a yellow oil,which was used in the next step without further purification. ESI-MS[M+H]⁺: 135.1.

Synthesis of dimethyl5-cyclopropylpyrazolo[1,5-a]pyridine-2,3-dicarboxylate

To a solution of 1-amino-4-cyclopropylpyridin-1-ium 2,6-dimethylbenzenesulfonate (4.2 g, 12.6 mmol) and dimethylbut-2-ynedioate (3.6 g, 25.22 mmol) in CH₃CN (60 mL) was added DBU (3.8g, 25.22 mmol) at 0° C. for 30 min. Then the resulting mixture wasstirred at RT for 16 h. The reaction mixture was concentrated to givethe crude, which was purified with silica gel chromatography (PE/EA=2/1)to give dimethyl 5-cyclopropylpyrazolo[1,5-a]pyridine-2, 3-dicarboxylate(2.5 g, yield: 72.4%) as a yellow oil. ESI-MS [M+H]⁺: 275.1.

Synthesis of 5-cyclopropylpyrazolo[1,5-a]pyridine-2-carboxylic Acid

A mixture of dimethyl 5-cyclopropylpyrazolo [1, 5-a] pyridine-2,3-dicarboxylate (1.5 g, 5.47 mmol) and 50% H₂SO₄ in dioxane (8 mL) washeated at 85° C. for 5 h. Water (20 mL) was added and the mixture wasextracted with EtOAc (50 mL×3). The combined organic layers were washedwith brine, dried over Na₂SO₄ and concentrated in vacuo to give thecrude, which was purified by silica gel chromatography (PE/EA=1/1) togive 5-cyclopropylpyrazolo [1,5-a]pyridine-2-carboxylic acid (600 mg,yield: 54.0%) as a white solid. ESI-MS [M+H]⁺: 203.1.

Synthesis of (5-cyclopropylpyrazolo[1,5-a]pyridin-2-yl)methanol

To a solution of 5-cyclopropylpyrazolo[1,5-a]pyridine-2-carboxylic acid(202 mg, 1.0 mmol) in THF (10 mL) was added LiAH₄ (1.5 mL, 1 M) at 0°C., the reaction mixture was stirred at 0° C. for 30 min. then warmed toRT and stirred for 4 h. The reaction was quenched by H₂O (10 mL)resulting in a precipitate. The filtrate was concentrated to give(5-cyclopropylpyrazolo[1,5-a]pyridin-2-yl)methanol (140 mg, yield:74.5%) as a yellow oil which was used in the next step without furtherpurification. ESI-MS [M+H]⁺: 189.1.

Synthesis of 2-(chloromethyl)-5-cyclopropylpyrazolo[1,5-a]pyridine

A mixture of (5-cyclopropylpyrazolo [1,5-a]pyridin-2-yl) methanol (140mg, 0.74 mmol) and SOCl₂ (3 mL) was stirred at 50° C. for 1 h. Thereaction mixture was concentrated to give the crude product2-(chloromethyl)-5-cyclopropylpyrazolo[1,5-a]pyridine (200 mg, crude) asa black oil which was used in the next step without purification. ESI-MS[M+H]⁺: 207.1.

Synthesis ofN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((5-cyclopropylpyrazolo[1,5-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(I-50)

A mixture of 2-(chloromethyl)-5-cyclopropylpyrazolo[1,5-a]pyridine (30mg, 0.15 mmol), N-((7-chloroimidazo [1, 5-a] pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide (42 mg, 0.15 mmol), Cs₂CO₃ (200 mg,0.61 mmol) in DMF (3 mL) was stirred at 50° C. for 16 h. Water (30 mL)was added and extracted with EtOAc (30 mL×3). The combined organiclayers were washed with brine, dried over Na₂SO₄, filtered, concentratedand purified by prep-HPLC to obtained product as a white solid (2.2 mg,yield: 3.3%). ESI-MS [M+H]⁺: 446.7. Purity: 100%. ¹H NMR (400 MHz,DMSO): δ 8.62-8.50 (m, 2H), 8.47 (d, J=8.0 Hz, 1H), 8.32 (s, 2H), 8.30(s, 1H), 8.23 (s, 1H), 7.87 (s, 1H), 7.78 (s, 1H), 7.32 (s, 1H), 6.65(d, J=8.0 Hz, 1H), 6.57 (dd, J=8.0, 2.0 Hz, 1H), 6.27 (s, 1H), 5.45 (s,2H), 4.55 (d, J=4.0 Hz, 2H), 1.99-1.93 (m, 1H), 1.02-0.95 (m, 2H),0.78-0.70 (m, 2H).

Synthesis of 5-cyclopropylpyridin-2-amine

To a solution of 5-bromopyridin-2-amine (50 g, 290 mmol) in toluene/H₂O(700 mL/70 mL) was added cyclopropylboronic acid (37.4 g, 435 mmol),Pd(OAc)₂ (6.49 g, 29.0 mmol), SPhos (12.8 g, 29.0 mmol) and K₃PO₄ (184.4g, 870 mmol). The reaction mixture was stirred at 95° C. for 14 h undernitrogen. Then the mixture was concentrated in vacuo. Water (400 mL) wasadded and the mixture was extracted with DCM (500 mL×2). The combinedorganic layers were concentrated to give the crude product, which waspurified by silica gel chromatography (PE/EtOAc=1/1) to give the5-cyclopropylpyridin-2-amine as a yellow solid (38 g, yield: 97%).ESI-MS [M+H]⁺: 135.2.

Synthesis of Ethyl 2-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)acetate

To a solution 5-cyclopropyl-4-methylpyridin-2-amine (30 g, 223.9 mmol)in EtOH (400 mL) was added ethyl 4-chloro-3-oxobutanoate (110 g, 671.7mmol) at RT. The resulting mixture was stirred at 90° C. for 16 h andthen concentrated in vacuo. H₂O (500 mL) was added, the pH value of themixture was adjusted to 8 by adding saturated NaHCO₃ solution, and thenthe mixture was extracted with EtOAc (400 mL×3). The combined organiclayers were washed with brine, dried over Na₂SO₄, and concentrated togive the crude product, which was purified by silica gel chromatography(DCM/MeOH=10/1) to give ethyl2-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)acetate (40 g, impure) as ablack solid. ESI-MS [M+H]⁺: 245.2.

Synthesis of 2-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)acetohydrazide

A mixture of ethyl 2-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)acetate(40 g, impure) and N₂H₄—H₂O (50 mL) in EtOH (300 mL) was stirred at 85°C. for 12 h. The mixture was then concentrated and purified by silicagel chromatography (DCM/MeOH=10/1) to give2-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)acetohydrazide (17.1 g,yield: 31.5% in 2 steps) as a yellow solid. ESI-MS [M+H]⁺: 231.1.

Synthesis of Ethyl2-(2-(2-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)acetyl)hydrazinyl)-2-oxoacetate

To a solution of2-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)acetohydrazide (17 g, 73.9mmol) and DIPEA (38 mL, 222 mmol) in DCM (300 mL) was added ethyl2-chloro-2-oxoacetate (15 g, 111 mmol) slowly at 0° C. The reactionmixture was stirred at RT for 2 h. Water (200 mL) was added and themixture was extracted with DCM (200 mL×2). The combined organic layerswere concentrated to give the crude product, which was purified bysilica gel chromatography (DCM/MeOH=10/1) to give (ethyl2-(2-(2-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)acetyl)hydrazinyl)-2-oxoacetate (17 g, yield: 70%) as ayellow solid. ESI-MS [M+H]⁺: 331.1.

Synthesis of Ethyl5-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1,3,4-oxadiazole-2-carboxylate

To a solution of ethyl2-(2-(2-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)acetyl)hydrazinyl)-2-oxoacetate (17 g, 51.5 mmol) and Et₃N (14 mL, 2 mmol) inDCM (300 mL) was added a solution of TsCl (11.8 g, 61.8 mmol) in DCM (50mL) at RT. The reaction mixture was stirred at this temperature for 16h. Water (200 mL) was added and the mixture was extracted with DCM (200mL×2). The combined organic layers were concentrated and purified bysilica gel chromatography (DCM/MeOH=10/1) to give2-(chloromethyl)-5-methylimidazo[1,2-a]pyridine (8.2 g, yield: 51%) as ayellow oil. ESI-MS [M+H]⁺: 313.2.

Synthesis of lithium5-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1,3,4-oxadiazole-2-carboxylate

A solution of ethyl5-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1,3,4-oxadiazole-2-carboxylate(8.0 g, 25.6 mmol) and LiOH H₂O (2.1 g, 51.2 mmol) in a mixed solvent ofTHF/MeOH/H₂O (50 mL/50 mL/50 mL) was stirred at RT for 2 h. THF andmethanol were removed in vacuo at 20° C. and the remaining H₂O phase waslyophilized to give lithium5-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1,3,4-oxadiazole-2-carboxylate(7.4 g, yield: 100%) as a yellow solid. This material was used directlyin the next step without further purification. ESI-MS [M+H]⁺: 285.1.

Synthesis ofN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-5-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1,3,4-oxadiazole-2-carboxamide(I-51)

A mixture of lithium5-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1,3,4-oxadiazole-2-carboxylate(7 g, 24 mmol), (7-chloroimidazo[1,5-a]pyridin-1-yl)methanamine (6.28 g,28.8 mmol), EDCI (9.2 g, 48 mmol), HOBT (6.48 g, 48 mmol) and DIPEA (12mL, 72 mmol) in DMF (100 mL) was stirred at 20° C. for 48 h. The mixturewas concentrated to remove DMF, diluted with DCM/MeOH (300 mL, 10/1(v/v)) and washed with H₂O (100 mL×2). The organic layer was separated,dried over Na₂SO₄, and concentrated in vacuo to give the crude product,which was purified by silica gel chromatography (DCM/MeOH=10/1) and thentriturated with methanol to giveN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-5-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1,3,4-oxadiazole-2-carboxamide (3.1 g, yield:28.7%) as a light yellow solid. ESI-MS [M+H]⁺: 448.2. Purity: 99%. ¹HNMR (400 MHz, DMSO): δ 9.73 (t, J=5.8 Hz, 1H), 8.32-8.29 (m, 3H), 7.83(d, J=1.0 Hz, 1H), 7.79 (s, 1H), 7.37 (d, J=9.3 Hz, 1H), 6.98 (dd,J=9.4, 1.7 Hz, 1H), 6.67 (dd, J=7.4, 2.1 Hz, 1H), 4.62 (d, J=5.9 Hz,2H), 4.42 (s, 2H), 1.98-1.85 (m, 1H), 0.97-0.85 (m, 2H), 0.75-0.59 (m,2H).

Example 52

Synthesis ofN-((7-bromoimidazo[1,5-a]pyridin-1-yl)methyl)-5-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1,3,4-oxadiazole-2-carboxamide(I-52)

A mixture of5-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1,3,4-oxadiazole-2-carboxylicacid (50 mg, 0.18 mmol), (7-bromoimidazo[1,5-a]pyridin-1-yl)methanaminehydrochloride (55 mg, 0.21 mmol), EDCI (70 mg, 0.35 mmol), HOBT (50 mg,0.35 mmol) and DIPEA (0.1 mL, 0.53 mmol) in DMF (3 mL) was stirred at50° C. for 16 h. Water (30 mL) was added and extracted with EtOAc (30mL×3). The combined organic layers concentrated and purified byprep-HPLC to giveN-((7-bromoimidazo[1,5-a]pyridin-1-yl)methyl)-5-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1,3,4-oxadiazole-2-carboxamide(3.0 mg, yield: 3.5%) as a light yellow solid. ESI-MS [M+H]⁺: 492.1.Purity: 96.8%. ¹H NMR (400 MHz, DMSO): δ 9.73 (t, J=5.9 Hz, 1H), 8.32(s, 2H), 8.25 (d, J=7.4 Hz, 1H), 8.00 (s, 1H), 7.79 (s, 1H), 7.37 (d,J=9.4 Hz, 1H), 6.98 (dd, J=9.3, 1.7 Hz, 1H), 6.74 (dd, J=7.4, 1.9 Hz,1H), 4.62 (d, J=5.9 Hz, 2H), 4.42 (s, 2H), 1.95-1.89 (m, 1H), 0.99-0.82(m, 2H), 0.68-0.66 (m, 2H).

Example 53

Synthesis ofN-((6-aminoimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(I-53)

To a solution of1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylicacid (60 mg, 0.21 mmol), 1-(aminomethyl)imidazo[1,5-a]pyridin-6-amine(51 mg, 0.32 mmol) and HATU (120 mg, 0.31 mmol) in DMF (5 mL) was addedDIPEA (81 mg, 0.63 mmol). The resulting reaction was stirred at RT for12 h. H₂O (25 mL) was added and the reaction was extracted with EtOAc(50 mL×3). The combined organic layers were washed with brine, driedover Na₂SO₄, concentrated in vacuo to give the crude, which was purifiedwith prep-TLC (DCM/MeOH=10/1) to give theN-((6-aminoimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(10 mg, yield: 11%) as a white solid. ESI-MS [M+H]⁺: 427.2. Purity:92.3%. ¹H NMR (400 MHz, DMSO): δ 8.47 (t, J=5.6 Hz, 1H), 8.32 (s, 1H),8.21 (s, 1H), 8.16-8.14 (m, 2H), 7.86 (s, 1H), 7.71 (s, 1H), 7.40-7.38(m, 1H), 7.32 (s, 1H), 7.00-6.97 (m, 1H), 6.32-6.30 (m, 1H), 5.38 (s,2H), 4.55 (d, J=5.6 Hz, 2H), 1.95-1.78 (m, 2H), 0.95-0.83 (m, 4H),0.70-0.60 (m, 4H).

Example 54

Synthesis of 6-aminopicolinonitrile

To a solution of 6-bromopyridin-2-amine (500 mg, 2.9 mmol) in DMF (10mL) was added Zn(CN)₂ (480 mg, 4.1 mmol) andtetrakis(triphenylphosphine)palladium(O) (335 mg, 0.29 mmol). Theresulting mixture was stirred at 80° C. under nitrogen for 3 h. Thereaction mixture was filtered through celite and the filtrate wasdiluted with H₂O (100 mL) and extracted with ethyl acetate (3×50 mL).The combined organic layers were washed with brine, dried over anhydroussodium sulfate and concentrated. The residue was purified by flashcolumn chromatography to give 6-aminopicolinonitrile (250 mg, yield:72%). ESI-MS [M+H]⁺: 120.1.

Synthesis of 2-(chloromethyl)imidazo[1,2-a]pyridine-5-carbonitrile

To a solution of 6-aminopicolinonitrile (200 mg, 1.67 mmol) in DMF (3mL) was added 1,3-dichloropropan-2-one (1.0 g, 8.33 mmol). The resultingmixture was stirred at 90° C. for 2.5 h. The reaction mixture wasdiluted with H₂O (50 mL), extracted with ethyl acetate (3×50 mL), Thecombined organic layers were washed with brine, dried over anhydroussodium sulfate and concentrated. The residue was purified by flashcolumn chromatography to give2-(chloromethyl)imidazo[1,2-a]pyridine-5-carbonitrile (150 mg, yield:47%). ESI-MS [M+H]⁺: 192.0.

Synthesis ofN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((5-cyanoimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(I-54)

To a solution of 2-(chloromethyl)imidazo[1,2-a]pyridine-5-carbonitrile(44 mg, 0.23 mmol) in DMF (3 mL) was added cesium carbonate (224 mg,0.69 mmol) andN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide(63 mg, 0.23 mmol). The resulting mixture was diluted with H₂O (30 mL),extracted with ethyl acetate (3×50 mL), The combined organic layers werewashed with brine, dried over anhydrous sodium sulfate and concentrated.The residue was purified by prep-HPLC to giveN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((5-cyanoimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(12.7 mg, yield: 12.8%). ESI-MS [M+H]⁺: 431.1. Purity: 99.08%. ¹H NMR(400 MHz, DMSO): δ 8.59 (t, J=5.8 Hz, 1H), 8.34-8.26 (m, 2H), 8.26 (s,1H), 8.14 (s, 1H), 7.94 (d, J=9.1 Hz, 1H), 7.87 (s, 1H), 7.84-7.79 (m,1H), 7.79-7.77 (m, 1H), 7.41-7.35 (m, 1H), 6.67-6.62 (m, 1H), 5.50 (s,2H), 4.56 (d, J=5.7 Hz, 2H).

Example 55

Synthesis ofN-((7-bromoimidazo[1,5-a]pyridin-1-yl)methyl)-1-((5-cyanoimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(I-75)

To a solution of 2-(chloromethyl)imidazo[1,2-a]pyridine-5-carbonitrile(49 mg, 0.26 mmol) in DMF (3 mL) was added cesium carbonate (250 mg,0.77 mmol) andN-((7-bromoimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide(83 mg, 0.26 mmol). The resulting mixture was diluted with H₂O (30 mL)and extracted with ethyl acetate (3×30 mL). The combined organic layerwere washed with brine, dried over anhydrous sodium sulfate andconcentrated. The residue was purified by prep-HPLC to giveN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((5-cyanoimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(21 mg, yield: 17%). ESI-MS [M+H]⁺: 475.1. Purity: 97.73%. ¹H NMR (400MHz, DMSO): δ 8.59 (t, J=5.6 Hz, 1H), 8.32 (s, 1H), 8.26 (s, 1H),8.26-8.22 (m, 1H), 8.14 (s, 1H), 7.97-7.92 (m, 2H), 7.87 (s, 1H),7.83-7.79 (m, 1H), 7.41-7.35 (m, 1H), 6.74-6.70 (m, 1H), 5.50 (s, 2H),4.55 (d, J=5.7 Hz, 2H).

Example 56

Synthesis ofN-((7-bromoimidazo[1,5-a]pyridin-1-yl)methyl)-1-((5-cyclopropylpyrazolo[1,5-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(I-56)

A mixture of 2-(chloromethyl)-5-cyclopropylpyrazolo[1, 5-a] pyridine (30mg, 0.15 mmol), N-((7-bromoimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide (48 mg, 0.15 mmol) and Cs₂CO₃ (200 mg,0.61 mmol) in DMF (3 mL) was stirred at 50° C. for 16 h. Water (30 mL)was added and extracted with EtOAc (30 mL×3). The combined organiclayers were washed with brine, dried over Na₂SO₄, filtered, concentratedand purified by prep-HPLC to giveN-((7-bromoimidazo[1,5-a]pyridin-1-yl)methyl)-1-((5-cyclopropylpyrazolo[1,5-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(10 mg, yield: 13%) as a white solid. ESI-MS [M+H]⁺: 490.0. Purity:86.77%. ¹H NMR (400 MHz, DMSO): δ 8.62-8.55 (m, 1H), 8.47 (d, J=8.0 Hz,1H), 8.32 (s, 1H), 8.25 (d, J=0.8 Hz, 1H), 8.23 (s, 1H), 7.95 (d, J=1.2Hz, 1H), 7.87 (s, 1H), 7.32 (s, 1H), 6.72 (dd, J=8.0, 2.0 Hz, 1H), 6.57(dd, J=8.0, 2.0 Hz, 1H), 6.27 (s, 1H), 5.45 (s, 2H), 4.55 (d, J=4.0 Hz,2H), 2.00-1.90 (m, 1H), 1.03-0.92 (m, 2H), 0.78-0.70 (m, 2H).

Example 57

Synthesis of Ethyl1-((5-chloro-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate

A mixture of5-chloro-2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine (190 mg,0.79 mmol), ethyl 1H-pyrazole-4-carboxylate (221 mg, 1.58 mmol) andCs₂CO₃ (769 mg, 2.36 mmol) in DMF (6 mL) was stirred at 60° C. for 3 h.Water (50 mL) was added and the mixture was extracted with EtOAc (100mL×3). The combined organic layers were concentrated and purified bysilica gel chromatography (EA/PE=2:3 to 10:1) to give ethyl1-((5-chloro-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate(220 mg, yield: 64%) as a white solid. ESI-MS [M+H]⁺: 345.2.

Synthesis of1-((5-chloro-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylicAcid

To a solution of1-((5-chloro-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate(220 mg, 0.64 mmol) in a mixed solvent of ethanol/THF/H₂O (3 mL/3 mL/1.5mL) was added LiOH H₂O (107 mg, 2.55 mmol). The mixture was stirred at60° C. for 3 h. Most of the solvent was removed and the residue wasdiluted with H₂O (10 mL), the pH value of mixture was adjusted to 4-5 byadding aqueous HCl (1 M). The solution was extracted with EtOAc (50mL×4). The combined organic layers were concentrated to give1-((5-chloro-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylicacid (160 mg, yield: 80%) as a white solid. ESI-MS [M+H]⁺: 317.2.

Synthesis ofN-((7-bromoimidazo[1,5-a]pyridin-1-yl)methyl)-1-((5-chloro-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(I-57)

A mixture of1-((5-chloro-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylicacid (63.2 mg, 0.2 mmol), (7-bromoimidazo[1,5-a]pyridin-1-yl)methanaminehydrochloride (52.4 mg, 0.2 mmol), HATU (190 mg, 0.5 mmol) and DIPEA(77.5 mg, 0.6 mmol) in DMF (3 mL) was stirred at RT for 3 h. Water (30mL) was added and the mixture was extracted with EtOAc (50 mL×3). Thecombined organic layers were concentrated and purified by prep-TLC(DCM:MeOH=8:1) to giveN-((7-bromoimidazo[1,5-a]pyridin-1-yl)methyl)-1-((5-chloro-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(19.9 mg, yield: 19%) as a white solid. ESI-MS [M+H]⁺: 524.1. Purity:92.44%. ¹H NMR (400 MHz, DMSO): δ 8.58 (t, J=5.6 Hz, 1H), 8.31 (s, 1H),8.24-8.22 (m, 2H), 7.94-7.86 (m, 3H), 7.49 (d, J=9.3 Hz, 1H), 6.97 (d,J=9.3 Hz, 1H), 6.71 (dd, J=7.4, 1.8 Hz, 1H), 5.45 (s, 2H), 4.54 (d,J=5.7 Hz, 2H), 2.14-2.09 (m 1H), 1.03-1.0 (m, 2H), 0.78-0.74 (m, 2H).

Example 58

Synthesis of 2-amino-4-chloropyridine 1-oxide

To a solution of 4-chloropyridin-2-amine (5.14 g, 40 mmol) in DCM (200mL) at 0° C. was added m-CPBA slowly. The reaction mixture was stirredat RT for 4 h. Water (100 mL) was added and the pH of the mixture wasadjusted to 8 by adding saturated NaHCO₃ solution. Then the H₂O layerwas extracted with DCM/CH₃OH (10:1, 100 mL×5). The combined organiclayers were concentrated to give 2-amino-4-chloropyridine 1-oxide (3.4g, yield: 61%) as a yellow solid, which was used in the next stepwithout further purification. ESI-MS [M+H]⁺: 145.1.

Synthesis of 6-amino-4-chloropicolinonitrile

A mixture of 2-amino-4-chloropyridine 1-oxide (1.74 g, 12 mmol), TMSCN(24 mL, 192 mmol) and TEA (26 mL, 192 mmol) in CH₃CN (20 mL) was stirredat 105° C. overnight in a sealed tube. Saturated aqueous NaHCO₃ wasadded to adjust the pH to 8, and then extracted with DCM (100 mL×2). Thecombined organic layers were concentrated and purified by silica gelchromatography (EA/PE=1/4) to give 6-amino-4-chloropicolinonitrile (1.16g, yield: 63%) as a yellow solid. ESI-MS [M+H]⁺: 154.1.

Synthesis of 6-(aminomethyl)-4-chloropyridin-2-amine

To a solution of 6-amino-4-chloropicolinonitrile (1.16 g, 7.6 mmol) indry THF (10 mL) was added BH₃ (1 M in THF, 19 mL) dropwise. The mixturewas stirred at RT overnight. Then the mixture was quenched with CH₃OHand stirred at RT for 1 h. the resulting mixture was then concentratedto give 6-(aminomethyl)-4-chloropyridin-2-amine (1.18 g, yield: 99%) asa yellow solid, which was used in the next step without furtherpurification. ESI-MS [M+H]⁺: 158.1.

Synthesis of N-((6-amino-4-chloropyridin-2-yl)methyl)formamide

A solution of 6-(aminomethyl)-4-chloropyridin-2-amine (1.18 g, 7.5mmol), HCOOH (20 mL) and EtOH (20 mL) was stirred at 80° C. for 2 h.Solvent was concentrated, H₂O (20 mL) was added, and the pH of themixture was adjusted to 8 by adding saturated aqueous NaHCO₃ solution.The mixture was then extracted with EtOAc (50 mL×5). The combinedorganic layers were concentrated to giveN-((6-amino-4-chloropyridin-2-yl)methyl)formamide (1.05 g, yield: 75%)as a white solid. ESI-MS [M+H]⁺: 186.1.

Synthesis of 7-chloroimidazo[1,5-a]pyridin-5-amine

A solution of N-((6-amino-4-chloropyridin-2-yl)methyl)formamide (1.6 g,8.6 mmol) in POCl₃ (15 mL) was stirred at 120° C. for 2 h. Solvent wasconcentrated and the residue was diluted with H₂O (20 mL). The pH of themixture was adjusted to 8 by adding saturated NaHCO₃ solution and thenextracted with EtOAc (100 mL×3). The combined organics were concentratedand purified by silica gel chromatography (CH₂Cl₂/CH₃OH=10/1) to give7-chloroimidazo[1,5-a]pyridin-5-amine (3.4 g, yield: 61%) as a graysolid. ESI-MS [M+H]⁺: 168.1

Synthesis ofN′-(7-chloro-1-formylimidazo[1,5-a]pyridin-5-yl)-N,N-dimethylformimidamide

A mixture of 7-chloroimidazo[1,5-a]pyridin-5-amine (155 mg, 0.92 mmol),DMF (203 mg, 2.76 mmol) and POCl₃ (3 mL) was stirred at 60° C. for 1 h.Then the reaction mixture was poured in to ice H₂O and NH₄OH was addedto adjust pH to about 8. The resulting mixture was extracted with EtOAc(30 mL×5). The combined organic layers were concentrated to giveN′-(7-chloro-1-formylimidazo[1,5-a]pyridin-5-yl)-N,N-dimethylformimidamide(220 mg, yield: 96%) as a yellow solid. ESI-MS [M+H]⁺: 251.1.

Synthesis of 5-amino-7-chloroimidazo[1,5-a]pyridine-1-carbaldehyde

A mixture ofN′-(7-chloro-1-formylimidazo[1,5-a]pyridin-5-yl)-N,N-dimethylformimidamide(220 mg, 0.88 mmol), CH₃OH (5 mL) and aqueous KOH (5 M, 1 mL) wasstirred at RT overnight. Water (20 mL) was added and the mixture wasextracted with EtOAc (50 mL×3). The combined organic layers wereconcentrated and purified by silica gel chromatography (CH₂Cl₂/CH₃H=9/1)to give 5-amino-7-chloroimidazo[1,5-a]pyridine-1-carbaldehyde (50 mg,yield: 29%) as an orange solid. ESI-MS [M+H]⁺: 196.1.

Synthesis ofN-((5-amino-7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-2-methylpropane-2-sulfinamide

A mixture of 5-amino-7-chloroimidazo[1,5-a]pyridine-1-carbaldehyde (22mg, 0.11 mmol), 2-methylpropane-2-sulfinamide (15.7 mg, 0.13 mmol) andTi(OEt)₄ (0.12 mL, 0.55 mmol) in THF (0.2 mL) was stirred at 80° C.overnight. After cooled to RT, NaBH₄ (20.8 mg, 0.55 mmol) was added. Thereaction mixture was stirred at RT for 3 h. Water (10 mL) and EtOAc (10mL) was added and the mixture was filtered. The filtration was extractedwith EtOAc (30 mL×3). The combined organic layers were concentrated andpurified by silica gel chromatography (CH₂Cl₂/CH₃OH=10/1) to giveN-((5-amino-7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-2-methylpropane-2-sulfinamide(10 mg, yield: 30%) as a yellow solid. ESI-MS [M+H]⁺: 313.1.

Synthesis of 1-(aminomethyl)-7-chloroimidazo[1,5-a]pyridin-5-amine

To a solution ofN-((5-amino-7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-2-methylpropane-2-sulfinamide(48 mg, 0.16 mmol) in CH₃OH (2 mL) was added HCl (4 M in dioxane, 0.25mL). The mixture was stirred at RT for 1 h, then concentrated to give1-(aminomethyl)-7-chloroimidazo[1,5-a]pyridin-5-amine (31 mg, yield:99%) as a yellow solid which was used in the next step withoutpurification. ESI-MS [M−16]⁺: 180.1.

Synthesis ofN-((5-amino-7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-methylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(I-58)

A mixture of 1-(aminomethyl)-7-chloroimidazo[1,5-a]pyridin-5-amine (22mg, 0.11 mmol),1-((6-methylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylicacid (28 mg, 0.11 mmol), HATU (84 mg, 0.22 mmol), and DIPEA (43 mg, 0.33mmol) in DMF (2 mL) was stirred at RT for 2 h. Water (10 mL) was addedand extracted with DCM/MeOH (30 mL×3, 10/1, (v/v)). The combined organiclayers were concentrated and purified by silica gel chromatography(DCM/CH₃OH=6/1) to giveN-((5-amino-7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-methylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(9 mg, yield: 9%) as a white solid. ESI-MS [M+H]⁺: 435.2. Purity: 100%.¹H NMR (400 MHz, DMSO): δ 8.50 (t, J=5.6 Hz, 1H), 8.31 (s, 1H), 8.27 (s,1H), 8.21 (s, 1H), 7.86 (s, 1H), 7.75 (s, 1H), 7.41 (d, J=9.2 Hz, 1H),7.10 (dd, J=9.2, 1.3 Hz, 1H), 7.03 (d, J=1.3 Hz, 1H), 6.84 (s, 2H), 5.64(d, J=1.8 Hz, 1H), 5.39 (s, 2H), 4.53 (d, J=5.7 Hz, 2H), 2.24 (s, 3H).

Example 59

Synthesis of 6-fluoropyridin-2-amine

A mixture of 6-fluoropyridin-2-amine (3 g, 26.8 mmol) andN-bromosuccinimide (5.25 g, 29.5 mmol) in dry CH₃CN (20 mL) was stirredat 0° C. for 2 h. Water (100 mL) was added and the mixture was extractedwith EtOAc (100 mL×3). The combined organic layers were concentrated andpurified by silica gel chromatography (EA/PE=1/5) to give5-bromo-6-fluoropyridin-2-amine (4.31 g, yield: 84.2%) as a white solid.ESI-MS [M+H]⁺: 191.0.

Synthesis of 5-cyclopropyl-6-fluoropyridin-2-amine

A solution of 5-bromo-6-fluoropyridin-2-amine (3.0 g, 15.8 mmol),cyclopropylboronic acid (2.04 mg, 23.7 mmol), Pd(OAc)₂ (354 mg, 1.58mmol), PCy₃ (886.2 mg, 3.16 mmol) and K₃PO₄ (6.7 g, 31.6 mmol) indioxane/H₂O (30 mL/3 mL) was stirred at 100° C. for 16 h. Then thereaction mixture was diluted with H₂O (50 mL) and extracted with EtOAc(100 mL×3). The combined organic layers were dried over Na₂SO₄ andconcentrated to give the desired compound5-cyclopropyl-6-fluoropyridin-2-amine (yellow oil, 2.2 g). ESI-MS[M+H]⁺: 153.2.

Synthesis of2-(chloromethyl)-6-cyclopropyl-5-fluoroimidazo[1,2-a]pyridine

A solution of 5-cyclopropyl-6-fluoropyridin-2-amine (1.5 g, 10 mmol) and1,3-dichloropropan-2-one (3.8 g, 30 mmol) in dry DMF (15 mL) was stirredat 90° C. for 2.5 h. Then the reaction mixture was diluted with H₂O (100mL) and extracted with EtOAc (100 mL×3). The combined organic layerswere dried over Na₂SO₄, concentrated and purified by columnchromatography (PE:EA=5:1) to give the desired product2-(chloromethyl)-6-cyclopropyl-5-fluoroimidazo[1,2-a]pyridine (325 mg,yield: 15%) as a yellow solid. ESI-MS [M+H]⁺: 225.1.

Synthesis ofN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-5-fluoroimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(I-59)

A solution of2-(chloromethyl)-6-cyclopropyl-5-fluoroimidazo[1,2-a]pyridine (22 mg,0.1 mmol),N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide(28 mg, 0.1 mmol), and Cs₂CO₃ (98 mg, 0.3 mmol) in dry DMF (2 mL) wasstirred at RT for 2 h. Then the reaction mixture was diluted with H₂O(20 mL) and extracted with EtOAc (30 mL×3). The combined organic layerswere dried over Na₂SO₄, concentrated and purified by columnchromatography (DCM/MeOH=15/1) to give the desired compoundN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-5-fluoroimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(17 mg, yield: 33%) as a yellow solid, ESI-MS [M+H]⁺: 446.2; [M/2+H]⁺:232.7. Purity: 97.80%. ¹H NMR (400 MHz, DMSO): δ 8.57 (t, J=5.7 Hz, 1H),8.30-8.28 (m, 2H), 8.21 (s, 1H), 7.85 (d, J=3.3 Hz, 2H), 7.76-7.76 (m,1H), 7.33 (d, J=9.3 Hz, 1H), 7.04-7.00 (m, 1H), 6.63 (dd, J=7.5, 2.1 Hz,1H), 5.41 (s, 2H), 4.54 (d, J=5.8 Hz, 2H), 2.04-2.00 (m, 1H), 0.97-0.94(m, 2H), 0.76-0.72 (m, 2H).

Example 60

Synthesis ofN-((7-bromoimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-5-fluoroimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(I-60)

A solution of2-(chloromethyl)-6-cyclopropyl-5-fluoroimidazo[1,2-a]pyridine (22 mg,0.1 mmol),N-((7-bromoimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide(32 mg, 0.1 mmol), and Cs₂CO₃ (98 mg, 0.3 mmol) in dry DMF (2 mL) wasstirred at RT for 2 h. Then the reaction mixture was diluted with H₂O(10 mL) and extracted with EtOAc (30 mL×3). The combined organic layerswere dried over Na₂SO₄, concentrated and purified by columnchromatography (DCM/MeOH=15/1) to give the desired compoundN-((7-bromoimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-5-fluoroimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(11 mg, yield: 22%) as a yellow solid. ESI-MS [M+H]⁺: 508.1; [M/2+H]⁺:254.7. Purity: 91.63%. ¹H NMR (400 MHz, DMSO): δ 8.58 (t, J=5.7 Hz, 1H),8.31 (s, 1H), 8.25-8.22 (m, 2H), 7.95 (s, 1H), 7.86 (d, J=3.8 Hz, 2H),7.34 (d, J=9.3 Hz, 1H), 7.03 (t, J=8.8 Hz, 1H), 6.72 (dd, J=7.4, 1.9 Hz,1H), 5.43 (s, 2H), 4.55 (d, J=5.7 Hz, 2H), 2.05-2.01 (m, 1H), 0.98-0.95(m, 2H), 0.82-0.65 (m, 2H).

Example 61

Synthesis of 5-cyclobutyl-2-methoxypyridine

A mixture of 5-bromo-2-methoxypyridine (4.0 g, 21.27 mmol),cyclobutylboronic acid (2.34 g, 23.40 mmol), Pd(dppf)Cl₂ (1.55 g, 2.13mmol) and Na₂CO₃ (2.93 g, 27.65 mmol) in toluene (100 mL) and H₂O (20mL) was stirred at 100° C. for 16 h. The reaction mixture wasconcentrated, diluted with EtOAc (100 mL) and filtered. The filtrate waswashed with H₂O (100 mL×1) and brine (100 mL×1), dried over Na₂SO₄,concentrated and purified by silica gel chromatography (EA/PE=1/60) togive 5-cyclobutyl-2-methoxypyridine (1.5 g, yield: 43%) as yellow oil.ESI-MS [M+H]⁺: 164.2.

Synthesis of 5-cyclobutylpyridin-2(1H)-one

A mixture of 5-cyclobutyl-2-methoxypyridine (1.5 g, 9.19 mmol) and HBr(15 mL, 40% (v/v) in H₂O) in EtOH (6 mL) was stirred for at 80° C. for48 h. The reaction mixture was cooled to RT, concentrated, neutralizedwith NaHCO₃ aqueous to adjust the pH to 7 and extracted with DCM/MeOH(60 mL×3, 10/1 (v/v)). The combined organics was washed with brine (150mL×1), dried over Na₂SO₄, concentrated and purified by silica gelchromatography (EA) to give 5-cyclobutylpyridin-2(1H)-one (260 mg,yield: 19%) as a yellow syrup. ESI-MS [M+H]⁺: 150.2.

Synthesis of 2-chloro-5-cyclobutylpyridine

A solution of 5-cyclobutylpyridin-2(1H)-one (260 mg, 1.74 mmol) in POCl₃(3 mL) was stirred at 130° C. for 1 h under microwave. The reactionmixture was concentrated and the residue was dissolved in EtOAc (100mL), washed with NaHCO₃ aqueous (50 mL×1) and brine (50 mL×1), driedover Na₂SO₄, concentrated and then purified by silica gel chromatography(EA/PE=1/50) to give 2-chloro-5-cyclobutylpyridine (250 mg, yield: 86%)as yellow oil. ESI-MS [M+H]⁺: 168.1.

Synthesis of N-(5-cyclobutylpyridin-2-yl)-1,1-diphenylmethanimine

A mixture of 2-chloro-5-cyclobutylpyridine (220 mg, 1.31 mmol),diphenylmethanimine (357 mg, 1.97 mmol), Pd₂(dba)₃ (120 mg, 0.131 mmol),BINAP (163 mg, 0.262 mmol) and t-BuONa (315 mg, 3.28 mmol) in toluene (8mL) was stirred at 100° C. for 16 h. The reaction mixture was thendiluted in EtOAc (100 mL) and filtered. The filtrate was washed with H₂O(50 mL×1), dried over Na₂SO₄, concentrated and purified by silica gelchromatography (EA/PE=1/8) to giveN-(5-cyclobutylpyridin-2-yl)-1,1-diphenylmethanimine (130 mg, yield:32%) as a yellow solid. ESI-MS [M+H]⁺: 313.2.

Synthesis of 5-cyclobutylpyridin-2-amine

A mixture of N-(5-cyclobutylpyridin-2-yl)-1, 1-diphenylmethanimine (130mg, 0.41 mmol) and HCl (2 mL, 2 M) in THF (4 mL) was stirred at RT for 2h. The reaction mixture was concentrated. Water (20 mL) was added andthe pH of the mixture was adjusted to 9 by adding saturated aqueousNaHCO₃ solution. This resulting mixture was extracted with DCM/MeOH (50mL×3, 10/1 (v/v)). The combined organics was washed with brine (100mL×1), dried over Na₂SO₄, concentrated and purified by prep-TLC (EA) togive 5-cyclobutylpyridin-2-amine (35 mg, yield: 57%) as a yellow syrup.ESI-MS [M+H]⁺: 149.2.

Synthesis of Ethyl 6-cyclobutylimidazo[1,2-a]pyridine-2-carboxylate

The mixture of 5-cyclobutylpyridin-2-amine (28 mg, 0.19 mmol) and ethyl3-bromo-2-oxopropanoate (41 mg, 0.20 mmol) in EtOH (5 mL) was heated toreflux and stirred for 18 h. The reaction mixture was concentrated andthe residue was dissolved in EtOAc (20 mL), washed with NaHCO₃ aqueous(20 mL×1) and brine (20 mL×1), dried over Na₂SO₄, concentrated andpurified by silica gel chromatography (EA) to give ethyl6-cyclobutylimidazo[1,2-a]pyridine-2-carboxylate (15 mg, yield: 33%) asa yellow solid. ESI-MS [M+H]⁺: 245.2.

Synthesis of (6-cyclobutylimidazo[1,2-a]pyridin-2-yl)methanol

To a stirred solution of LiAlH₄ (19 mg, 0.49 mmol) in THF (2 mL) wasadded dropwise the solution of6-cyclobutylimidazo[1,2-a]pyridine-2-carboxylate (15 mg, 0.061 mmol) inTHF (1 mL) at −78° C. The mixture was stirred at −78° C. for 30 min. Thereaction mixture was then quenched with Na₂SO₄.10H₂O and filtered. Thefiltrate was washed with THF (10 mL) and concentrated to give(6-cyclobutylimidazo[1,2-a]pyridin-2-yl)methanol (8 mg, yield: 64%) as ayellow solid which was used in the next step without purification.ESI-MS [M+H]⁺: 203.2.

Synthesis of 2-(chloromethyl)-6-cyclobutylimidazo[1,2-a]pyridine

To a stirred solution of(6-cyclobutylimidazo[1,2-a]pyridin-2-yl)methanol (8 mg, 0.039 mmol) inDCM (1 mL) was added SOCl₂ (47 mg, 0.39 mmol) in DCM (0.5 mL). Themixture was stirred at RT for 1 h. The reaction mixture was concentratedto give 2-(chloromethyl)-6-cyclobutylimidazo[1,2-a]pyridine (10 mg,yield: 100%) as a yellow solid. ESI-MS [M+H]⁺: 221.1.

Synthesis ofN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclobutylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(I-61)

The mixture of 2-(chloromethyl)-6-cyclobutylimidazo[1,2-a]pyridine (10mg, 0.045 mmol),N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide(12 mg, 0.045 mmol) and Cs₂CO₃ (30 mg, 0.09 mmol) in DMF (2 mL) wasstirred at RT for 2 h. Water (10 mL) was added and the mixture wasextracted with EtOAc/THF (15 mL×3, 5/1 (v/v)). The combined organiclayers were washed with brine (40 mL×3), dried over Na₂SO₄, concentratedand purified by prep-TLC (DCM/MeOH=10/1) to giveN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclobutylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(8 mg, yield: 38%) as a white solid. ESI-MS [M+H]⁺: 460.2. Purity:95.58%. ¹H NMR (400 MHz, DMSO): δ 8.57 (t, J=5.7 Hz, 1H), 8.34 (s, 1H),8.30 (m, 2H), 8.20 (s, 1H), 7.86 (s, 1H), 7.77 (m, 2H), 7.44 (d, J=9.3Hz, 1H), 7.18 (dd, J=9.3, 1.7 Hz, 1H), 6.64 (dd, J=7.4, 2.1 Hz, 1H),5.39 (s, 2H), 4.55 (d, J=5.8 Hz, 2H), 3.50 (m, 1H), 2.28 (m, 2H), 2.04(m, 3H), 1.83 (m, 1H).

Example 62

Synthesis of Ethyl 2-(chloromethyl)imidazo[1,2-a]pyridine-5-carboxylate

A mixture of ethyl 6-aminopicolinate (166 mg, 1.0 mmol) and 1,3-dichloropropan-2-one (630 mg, 5.0 mmol) in dry DMF (10 mL) was stirredat 95° C. for 6 h. Water (100 mL) was added and the mixture wasextracted with EtOAc (50 mL×3). The combined organic layers wereconcentrated and purified by silica gel chromatography (EA/PE=1/1) togive ethyl 2-(chloromethyl)imidazo[1,2-a]pyridine-5-carboxylate (70 mg,yield: 29%) as a yellow oil. ESI-MS [M+H]⁺: 239.1.

Synthesis of Ethyl2-((4-((7-chloroimidazo[1,5-a]pyridin-1-yl)methylcarbamoyl)-1H-pyrazol-1-yl)methyl)imidazo[1,2-a]pyridine-5-carboxylate

A mixture of ethyl 2-(chloromethyl)imidazo[1,2-a]pyridine-5-carboxylate(70 mg, 0.29 mmol),N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide(80 mg, 0.29 mmol) and Cs₂CO₃ (270 mg, 0.87 mmol) in DMF (5 mL) wasstirred at RT for 4 h. Water (30 mL) was added and extracted with EtOAc(50 mL×3). The combined organic layers were concentrated and purified byprep-TLC (DCM/MeOH=10/1) to give ethyl2-((4-((7-chloroimidazo[1,5-a]pyridin-1-yl)methylcarbamoyl)-1H-pyrazol-1-yl)methyl)imidazo[1,2-a]pyridine-5-carboxylate(90 mg, yield: 65%) as a yellow solid. ESI-MS [M+H]⁺: 478.1.

Synthesis ofN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((5-(hydroxymethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(I-62)

To a solution of ethyl2-((4-((7-chloroimidazo[1,5-a]pyridin-1-yl)methylcarbamoyl)-1H-pyrazol-1-yl)methyl)imidazo[1,2-a]pyridine-5-carboxylate(30 mg, 0.06 mmol) in dry THF (5 mL) was added LiAlH₄ (7 mg, 0.18 mmol)at 0° C. and the mixture was stirred at 0° C. for 10 min. Water (10 mL)was added to quench the reaction and extracted with EtOAc (30 mL×3). Thecombined organic layers were concentrated and purified by prep-TLC(DCM/MeOH=10/1) to giveN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((5-(hydroxymethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(16.5 mg, yield: 63.5%) as a light yellow solid. ESI-MS [M+H]⁺: 436.1.Purity: 95.3%. ¹H NMR (400 MHz, DMSO): δ 8.59 (s, 1H), 8.30 (d, J=6.7Hz, 2H), 8.23 (s, 1H), 7.84 (d, J=9.7 Hz, 2H), 7.78 (s, 1H), 7.47 (d,J=9.1 Hz, 1H), 7.33-7.20 (m, 1H), 6.91 (d, J=6.6 Hz, 1H), 6.64 (dd,J=7.5, 2.1 Hz, 1H), 5.67 (t, J=5.7 Hz, 1H), 5.44 (s, 2H), 4.71 (d, J=5.5Hz, 2H), 4.55 (d, J=5.8 Hz, 2H).

Example 63

Synthesis of 2-(chloromethyl)-5-methoxyimidazo[1,2-a]pyridine

A solution of 6-methoxypyridin-2-amine (500 mg, 4.1 mmol) and1,3-dichloropropan-2-one (2.58 g, 20.5 mmol) in DMF (10 mL) was stirredat 90° C. for 2 h. Then the reaction mixture was diluted with H₂O (100mL) and extracted with EtOAc (100 mL×3). The combined organic layerswere dried over Na₂SO₄, concentrated and purified by columnchromatography (CH₂Cl₂/MeOH=3/1) to give the desired product2-(chloromethyl)-5-methoxyimidazo[1,2-a]pyridine (200 mg, yield: 25%) asbrown oil. ESI-MS [M+H]⁺: 197.1.

Synthesis ofN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((5-methoxyimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(I-63)

A solution of 2-(chloromethyl)-5-methoxyimidazo[1,2-a]pyridine (36 mg,0.18 mmol),N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide(50 mg, 0.18 mmol) and Cs₂CO₃ (235 mg, 0.72 mmol) in DMF (3 mL) wasstirred at RT for 2 h. Water (30 mL) was added and extracted with EtOAc(50 mL×3). The combined organic layers were dried over Na₂SO₄,concentrated and purified by column chromatography (CH₂Cl₂/MeOH=10/1) togive the desired compoundN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((5-methoxyimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(20 mg, yield: 28%) as a white solid. ESI-MS [M+H]⁺: 436.1. Purify:96.0%. ¹H NMR (400 MHz, DMSO): δ 8.58 (t, J=5.7 Hz, 1H), 8.32-8.27 (m,2H), 8.22 (s, 1H), 7.85 (s, 1H), 7.78 (s, 1H), 7.66 (s, 1H), 7.33-7.27(m, 1H), 7.14 (d, J=9.0 Hz, 1H), 6.66-6.62 (m, 1H), 6.35 (d, J=7.4 Hz,1H), 5.41 (s, 2H), 4.55 (d, J=5.7 Hz, 2H), 4.07 (s, 3H).

Example 64

Synthesis ofN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-methylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(I-64)

To a solution of1-((6-methylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylicacid (128 mg, 0.5 mmol), (7-chloroimidazo[1,5-a]pyridin-1-yl)methanaminehydrochloride (141 mg, 0.65 mmol) and HATU (285 mg, 0.75 mmol) in DMF(10 mL) was added DIPEA (323 mg, 2.5 mmol). The resulting reaction wasstirred at RT for 12 h. H₂O (25 mL) was added to the reaction andextracted with EtOAc (25 mL×4). The combined organic layers were washedwith brine, dried over Na₂SO₄ and concentrated in vacuo to give thecrude, which was purified with prep-TLC (DCM/MeOH=10/1) to give theN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-methylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(55 mg, yield: 26%) as a white solid. ESI-MS [M+H]⁺: 420.1. Purity:96.6%. ¹H NMR (400 MHz, DMSO): δ 8.59 (s, 1H), 8.35-8.30 (m, 4H), 8.22(s, 1H), 7.89 (s, 1H), 7.78-7.76 (m, 2H), 7.41 (d, J=9.0 Hz, 1H), 7.11(d, J=9.0 Hz, 1H), 6.65 (d, J=6.8 Hz, 1H), 5.39 (s, 2H), 4.55 (d, J=5.2Hz, 2H), 2.25 (s, 3H).

Example 65

Synthesis of 1-benzyl 6-methyl 3-oxohexanedioate

To a solution of benzyl acetate (1.5 g, 10 mmol) in THF (10 mL) wasadded LDA (1 M, 15 mmol) at −78° C. and stirred for 1 h (solution A). Toa solution of 4-methoxy-4-oxobutanoic acid (1.58 g, 12 mmol) in THF (10mL) was added CDI (1.94 g, 12 mmol) and stirred at RT for 30 min(solution B). Solution B was added to solution A at −78° C. and stirredfor another 2 h. Saturated NH₄Cl (100 mL) was added to quenched thereaction and the reaction mixture was extracted with EtOAc (100 mL×3).The combined organics were concentrated and purified by silica gelchromatography (EA/PE=1/10) to give 1-benzyl 6-methyl 3-oxohexanedioate(500 mg, yield: 19%) as a colorless oil. ESI-MS [M+H]⁺: 265.1.

Synthesis of 1-benzyl 6-methyl(E)-2-((dimethylamino)methylene)-3-oxohexanedioate

A solution of 1-benzyl 6-methyl 3-oxohexanedioate (490 mg, 1.86 mmol) inDMFDMA (443 mg, 3.72 mmol) was heated to 80° C. for 2 h. The resultingmixture was concentrated to give 1-benzyl 6-methyl(E)-2-((dimethylamino)methylene)-3-oxohexanedioate (600 mg, crude) as ayellow oil which was used in the next step without purification. ESI-MS[M+H]⁺: 320.1.

Synthesis of benzyl 3-(3-methoxy-3-oxopropyl)-1H-pyrazole-4-carboxylate

To a solution of 1-benzyl 6-methyl(E)-2-((dimethylamino)methylene)-3-oxohexanedioate (600 mg, 1.86 mmol)in MeOH (6 mL) was added hydrazine hydrochloride (255 mg, 3.72 mmol).The mixture was stirred at RT for 16 h. The reaction was concentrated togive the crude, which was purified by silica gel chromatography(EA/PE=1/1) to give benzyl3-(3-methoxy-3-oxopropyl)-1H-pyrazole-4-carboxylate (384 mg, yield: 64%for two steps) as a yellow oil. ESI-MS [M+H]⁺: 289.1.

Synthesis of benzyl1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-3-(3-methoxy-3-oxopropyl)-1H-pyrazole-4-carboxylate

To a solution of benzyl3-(3-methoxy-3-oxopropyl)-1H-pyrazole-4-carboxylate (90 mg, 0.31 mmol)and 2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine (78 mg, 0.38mmol) in DMF (5 mL) was added CsCO₃ (302 mg, 0.93 mmol) at RT. Themixture was stirred at RT for 16 h. The reaction was diluted with H₂O(30 mL) and extracted with ethyl acetate (3×50 mL). The combined organiclayers were washed with brine, dried over sodium sulfate andconcentrated. The residue was purified by prep-TLC (MeOH/DCM=1/15) togive benzyl1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-3-(3-methoxy-3-oxopropyl)-1H-pyrazole-4-carboxylate(70 mg, yield: 50%) as a yellow oil. ESI-MS [M+H]⁺: 459.1.

Synthesis of1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-3-(3-methoxy-3-oxopropyl)-1H-pyrazole-4-carboxylicAcid

To a solution of benzyl1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-3-(3-methoxy-3-oxopropyl)-1H-pyrazole-4-carboxylate(100 mg, 0.22 mmol) in MeOH (10 mL) was added Pd/C (10%, 30 mg). Themixture was stirred at RT for 3 h under H₂. The mixture was filtered andconcentrated to give1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-3-(3-methoxy-3-oxopropyl)-1H-pyrazole-4-carboxylicacid (67 mg, 83%) as a white solid. ESI-MS [M+H]⁺: 369.1.

Synthesis of Methyl3-(4-(((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazol-3-yl)propanoate(I-65)

To a solution of1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-3-(3-methoxy-3-oxopropyl)-1H-pyrazole-4-carboxylicacid (80 mg, 0.22 mmol) and(7-chloroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride (56 mg,0.26 mmol) in dry DMF (4 mL) was added HATU (125 mg, 0.33 mmol) andDIPEA (114 mg, 0.88 mmol) at RT. The reaction was stirred at RT for 3 h.Water (20 mL) was added and the mixture was extracted with EtOAc (30mL×3). The organic layers were washed with brine (50 mL), dried oversodium sulfate, and concentrated. The crude residue was purified byprep-TLC (DCM/MeOH=10/1) to give methyl3-(4-(((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazol-3-yl)propanoate(70 mg, yield: 61%) as a yellow solid. ESI-MS [M+H]⁺: 532.2. Purity:95.2%. ¹H NMR (400 MHz, DMSO): δ 8.53 (t, J=5.7 Hz, 0.3H), 8.43-8.38 (m,0.7H), 8.36-8.27 (m, 3H), 8.15 (s, 0.7H), 7.92 (s, 0.3H), 7.84-7.67 (m,1.75H), 7.58 (s, 0.3H), 7.40-7.35 (m, 1H), 7.03-6.93 (m, 1H), 6.66-6.63(m, 1H), 5.42 (s, 0.6H), 5.28 (s, 1.4H), 4.64-4.47 (m, 2H), 3.57-3.56(m, 3H), 3.29-3.19 (m, 0.6H), 3.17-2.99 (m, 1.4H), 2.74-2.55 (m, 2H),1.97-1.84 (m, 1H), 0.94-0.89 (m, 2H), 0.68-0.64 (m, 2H).

Example 66

Synthesis of1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-((7-ethynylimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide(I-66)

A solution of1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylicacid (68 mg, 0.24 mmol),(7-ethynylimidazo[1,5-a]pyridin-1-yl)methanamine (50 mg, 0.24 mmol),HATU (183 mg, 0.48 mmol) and DIPEA (93 mg, 0.72 mmol) in DMF (3 mL) wasstirred at RT for 2 h. Then the reaction mixture was diluted with H₂O(50 mL) and extracted with EtOAc (50 mL×3). The combined organic layerswere dried over Na₂SO₄, concentrated and purified by columnchromatography (CH₂Cl₂/MeOH=10/1) to give the desired compound1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-((7-ethynylimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide(40 mg, yield: 38%) as a white solid. ESI-MS [M+H]⁺: 436.2. Purity:100%. ¹H NMR (400 MHz, DMSO): δ 8.59 (t, J=5.7 Hz, 1H), 8.34-8.31 (m,2H), 8.26-8.22 (m 1H), 8.20 (s, 1H), 7.88 (s, 1H), 7.86 (s, 1H), 7.71(s, 1H), 7.39 (d, J=9.4 Hz, 1H), 7.01-6.97 (m, 1H), 6.59-6.55 (m, 1H),5.38 (s, 2H), 4.58 (d, J=5.8 Hz, 2H), 4.26 (s, 1H), 1.95-1.88 (m, 1H),0.93-0.88 (m, 2H), 0.68-0.64 (m, 2H).

Example 67

Synthesis of1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-((7-ethylimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide(I-67)

A solution of1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylicacid (64 mg, 0.23 mmol), (7-ethylimidazo[1,5-a]pyridin-1-yl)methanaminehydrochloride (49 mg, 0.23 mmol), HATU (175 mg, 0.46 mmol) and DIPEA (90mg, 0.69 mmol) in DMF (3 mL) was stirred at RT for 2 h. Then thereaction mixture was diluted with H₂O (30 mL) and extracted with EtOAc(30 mL×3). The combined organic layers were dried over Na₂SO₄,concentrated and purified by column chromatography (CH₂Cl₂/MeOH=10/1) togive the desired compound1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-((7-ethylimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide(50 mg, yield: 49%) as a white solid. ESI-MS [M+H]⁺: 440.2. Purity: 97%.¹H NMR (400 MHz, DMSO): δ 8.47 (t, J=5.5 Hz, 1H), 8.32 (s, 1H),8.22-8.16 (m, 3H), 7.86 (s, 1H), 7.71 (s, 1H), 7.42-7.32 (m, 2H),7.01-6.96 (m, 1H), 6.52-6.48 (m, 1H), 5.38 (s, 2H), 4.56 (d, J=5.6 Hz,2H), 3.33-3.29 (m, 2H), 1.94-1.88 (m, 1H), 1.14 (t, J=7.5 Hz, 3H),0.93-0.88 (m, 2H), 0.69-0.63 (m, 2H).

Example 68

Synthesis ofN-((7-bromoimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methyl)-1H-pyrazole-4-carboxamide(I-68)

A solution of1-((6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methyl)-1H-pyrazole-4-carboxylicacid (48 mg, 0.17 mmol), (7-bromoimidazo[1,5-a]pyridin-1-yl)methanaminehydrochloride (45 mg, 0.17 mmol), HATU (134 mg, 0.35 mmol) and DIPEA (65mg, 0.53 mmol) in DMF (3 mL) was stirred at RT for 2 h. Then thereaction mixture was diluted with H₂O (30 mL) and extracted with EtOAc(50 mL×3). The combined organic layers were dried over Na₂SO₄,concentrated and purified by column chromatography (CH₂Cl₂/MeOH=8/1) togive the desired compoundN-((7-bromoimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methyl)-1H-pyrazole-4-carboxamide(20 mg, yield: 24%) as a white solid. ESI-MS [M+H]⁺: 491.1. Purity: 93%.¹H NMR (400 MHz, DMSO): δ 8.56 (t, J=5.7 Hz, 1H), 8.31 (s, 1H),8.26-8.19 (m, 2H), 8.08 (s, 1H), 7.96-7.90 (m, 2H), 7.85 (s, 1H), 7.09(d, J=9.5 Hz, 1H), 6.74-6.69 (m, 1H), 5.41 (s, 2H), 4.54 (d, J=5.7 Hz,2H), 2.20-2.14 (m, 1H), 1.09-1.03 (m, 2H), 0.99-0.93 (m, 2H).

Example 69

Synthesis of 2-(chloromethyl)imidazo[1,2-a]pyridine

A mixture of pyridin-2-amine (600 mg, 6.4 mmol) and 1,3-dichloropropan-2-one (4.0 g, 32.0 mmol) in dry DMF (10 mL) was stirredat 95° C. for 6 h. Water (100 mL) was added and the mixture wasextracted with EtOAc (80 mL×3). The combined organic layers wereconcentrated and purified by silica gel chromatography (EA/PE=1/1) togive 2-(chloromethyl)imidazo[1,2-a]pyridine (80 mg, yield: 7.5%) as ayellow oil. ESI-MS [M+H]⁺: 167.1.

Synthesis ofN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-(imidazo[1,2-a]pyridin-2-ylmethyl)-1H-pyrazole-4-carboxamide(I-69)

A mixture of 2-(chloromethyl)imidazo[1,2-a]pyridine (80 mg, 0.48 mmol),N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide(130 mg, 0.48 mmol) and Cs₂CO₃ (469 mg, 1.44 mmol) in DMF (5 mL) wasstirred at RT for 3 h. Water (50 mL) was added and extracted with EtOAc(50 mL×3). The combined organic layer were concentrated and purified byprep-TLC (DCM/MeOH=10/1) to giveN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-(imidazo[1,2-a]pyridin-2-ylmethyl)-1H-pyrazole-4-carboxamide(27 mg, yield: 14%) as a white solid. ESI-MS [M+H]⁺: 406.2. Purity:99.6%. ¹H NMR (400 MHz, DMSO): δ 8.59 (t, J=5.7 Hz, 1H), 8.51 (d, J=6.8Hz, 1H), 8.30 (d, J=7.1 Hz, 2H), 8.23 (s, 1H), 7.85 (d, J=14.5 Hz, 2H),7.78 (s, 1H), 7.49 (d, J=9.1 Hz, 1H), 7.27-7.18 (m, 1H), 6.87 (t, J=6.7Hz, 1H), 6.65 (dd, J=7.4, 2.0 Hz, 1H), 5.42 (s, 2H), 4.55 (d, J=5.7 Hz,2H).

Example 70

Synthesis of Ethyl5-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1,3,4-thiadiazole-2-carboxylate

A mixture of ethyl2-(2-(2-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)acetyl)hydrazinyl)-2-oxoacetate(330 mg, 1.0 mmol) and Lawesson's Regent (600 mg, 1.5 mmol) in CH₃CN (20mL) was stirred at 50° C. for 16 h under N₂. The mixture wasconcentrated and purified by silica gel chromatography (DCM/MeOH=10/1)to give ethyl5-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1,3,4-thiadiazole-2-carboxylate(280 mg, yield: 85.4%) as a yellow oil. ESI-MS [M+H]⁺: 329.1

Synthesis of lithium5-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1,3,4-thiadiazole-2-carboxylate

A solution of ethyl5-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1,3,4-thiadiazole-2-carboxylate(280 mg, 0.85 mmol) and LiOH.H₂O (70 mg, 1.70 mmol) in THF/MeOH/H₂O (2mL/2 mL/2 mL) was stirred at 50° C. for 2 h. The mixture wasconcentrated to give lithium5-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1,3,4-thiadiazole-2-carboxylate(320 mg, crude) as a yellow solid. ESI-MS [M+H]⁺: 301.1.

Synthesis ofN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-5-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1,3,4-thiadiazole-2-carboxamide(I-70)

A mixture of5-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1,3,4-thiadiazole-2-carboxylicacid (100 mg, crude), (7-chloroimidazo[1,5-a]pyridin-1-yl)methanaminehydrochloride (72 mg, 0.33 mmol), EDCI (130 mg, 0.66 mmol), HOBT (90 mg,0.66 mmol) and DIPEA (0.2 mL, 0.99 mmol) in DMF (4 mL) was stirred at50° C. for 16 h. Water (30 mL) was added and extracted with EtOAc (50mL×3). The combined organic layers were concentrated and purified byprep-HPLC to giveN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-5-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1,3,4-thiadiazole-2-carboxamide(12.1 mg, yield: 7.9%) as a light yellow solid. ESI-MS [M+H]⁺: 464.1.Purity: 95.4%. ¹H NMR (400 MHz, DMSO): δ 9.62 (t, J=5.9 Hz, 1H), 8.40(s, 1H), 8.35-8.26 (m, 2H), 7.91-7.80 (m, 2H), 7.49 (d, J=9.3 Hz, 1H),7.13 (d, J=9.4 Hz, 1H), 6.67 (dd, J=7.5, 2.1 Hz, 1H), 4.74-4.48 (m, 4H),1.99-1.93 (m, 1H), 1.00-0.88 (m, 2H), 0.71-0.69 (m, 2H).

Example 71

Synthesis of Ethyl 2-amino-5-bromonicotinate

To a solution of ethyl 2-aminonicotinate (500 mg, 3.00 mmol) in dry MeCN(20 mL) was added NBS (643 mg, 3.6 mmol) slowly at RT. The resultingmixture was stirred at RT for 1 h. The reaction was then quenched withH₂O (30 mL) and extracted with EtOAc (30 mL×3). The combined organiclayers were washed with brine, dried over Na₂SO₄, and concentrated invacuo to give the crude product of ethyl 2-amino-5-bromonicotinate (700mg, yield: 95.2%) as a white solid, which was used in the next stepwithout purification. ESI-MS [M+H]⁺: 245.0.

Synthesis of Ethyl 2-amino-5-cyclopropylnicotinate

A mixture ethyl 2-amino-5-bromonicotinate (700 mg, 2.85 mmol),cyclopropylboronic acid (728 mg, 8.5 mmol), Pd(OAc)₂ (140 mg, 0.05mmol), K₃PO₄ (3 g, 14.2 mmol) and PCy₃ (0.3 g, 1.14 mmol) indioxance/H₂O (50 mL/5 mL) was stirred at 95° C. for 12 h in N₂. Theresulting mixture was quenched with H₂O (40 mL), extracted with EtOAc(50 mL×3). The combined organic layers were washed with brine, driedwith Na₂SO₄ and concentrated in vacuo to give the crude, which waspurified with silica gel chromatography with PE/EA (1/1) to give ethyl2-amino-5-cyclopropylnicotinate (500 mg, 86% yield) as a white solid.ESI-MS [M+H]⁺: 207.1. Purity: 95%.

Synthesis of Ethyl2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-carboxylate

To a solution of ethyl 2-amino-5-cyclopropylnicotinate (500 mg, 1.94mmol) in DMF (10 mL) was added 1,3-dichloropropan-2-one (986 mg, 77.7mmol) at 95° C. for 3 h. Water (50 mL) was added and the pH of thereaction was adjusted to 8 with NaHCO₃ and then extracted with EtOAc (30mL×3). The combined organic layers were washed with brine, dried overNa₂SO₄ and concentrated in vacuo to give the crude, which was purifiedwith silica gel chromatography (EtOAc/PE=1/2) to give ethyl2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-carboxylate (550mg, yield: 65.3%) as a white solid. ESI-MS [M+H]⁺: 278.7. Purity: 90%.

Synthesis of Ethyl2-((4-(((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-pyrazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-carboxylate(I-71)

A mixture of ethyl2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-carboxylate (173mg, 0.6 mmol) in DMF (3 mL) was addedN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide(138 mg, 0.5 mmol) and Cs₂CO₃ (406 mg, 1.25 mmol). The resulting mixturewas stirred at RT for 3 h. The reaction was quenched with H₂O (30 mL)and extracted with EtOAc (30 mL×3). The combined organic layers werewashed with brine, dried over Na₂SO₄ and concentrated in vacuo to givethe crude, which was purified with prep-TLC (DCM/MeOH=10/1) to give theethyl2-((4-(((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-pyrazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-carboxylate(10 mg, yield: 3.2%) as a white solid. ESI-MS [M+H]⁺: 518.2. Purity:91.3%. ¹H NMR (400 MHz, DMSO): δ 8.63-8.49 (m, 2H), 8.31-8.29 (m, 2H),8.21 (s, 1H), 7.89 (s, 1H), 7.78 (d, J=1.9 Hz, 1H), 7.75 (s, 1H), 7.60(d, J=1.7 Hz, 1H), 6.64 (dd, J=7.5, 2.1 Hz, 1H), 5.45 (s, 2H), 4.55 (d,J=5.7 Hz, 2H), 4.33 (q, J=7.1 Hz, 2H), 2.03-1.96 (m, 1H), 1.31 (t, J=7.1Hz, 3H), 1.00-0.86 (m, 2H), 0.75-0.59 (m, 2H).

Example 72

Synthesis of2-((4-(((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-pyrazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-carboxylicacid (I-72)

To a solution of ethyl2-((4-(((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-pyrazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-carboxylate(40 mg, 0.077 mmol) in EtOH/THF/H₂O (2 mL/2 mL/1 mL) was added NaOH (0.5mL, 1 M), then the reaction was stirred at RT for 1 h. Most of thesolvent was removed and the residue was diluted with H₂O (3 mL). The pHof mixture was adjusted to 4-5 by adding HCl aqueous (1 M). Theresulting mixture was concentrated to give the crude, which was purifiedby prep-HPLC to give2-((4-(((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-pyrazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-carboxylate(9.7 mg, 26% yield) as a white solid. ESI-MS [M+H]⁺: 490.1. Purity:97.9%. ¹H NMR (400 MHz, DMSO): δ 8.66-8.54 (m, 2H), 8.34-8.27 (m, 2H),8.25 (s, 1H), 7.90 (s, 1H), 7.84 (s, 1H), 7.79-7.74 (m, 1H), 7.70 (d,J=1.7 Hz, 1H), 6.64 (dd, J=7.5, 2.1 Hz, 1H), 5.49 (s, 2H), 4.56 (d,J=5.7 Hz, 2H), 2.08-2.00 (m, 1H), 0.99-0.94 (m, 2H), 0.74-0.70 (m, 2H).

Example 73

Synthesis of3-(4-(((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazol-3-yl)propanoicacid (I-73)

To a solution of methyl3-(4-(((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazol-3-yl)propanoate(53 mg, 0.1 mmol) in MeOH/H₂O (2 mL/0.5 mL) was added aqueous NaOH (4 M,0.1 mL). The reaction was stirred at RT for 4 h. The pH of mixture wasadjusted to 4 by add in HCl (1 M). After concentrating the mixture, thecrude product was purified by prep-HPLC to give3-(4-(((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazol-3-yl)propanoicacid (40 mg, yield: 77%) as a white solid. ESI-MS [M+H]⁺: 518.1. Purity:97.7%. ¹H NMR (400 MHz, DMSO): δ 9.31 (s, 2H), 8.37-8.24 (m, 3H), 8.03(s, 1H), 7.80 (d, J=1.0 Hz, 1H), 7.71 (s, 1H), 7.39 (d, J=9.3 Hz, 1H),6.99 (dd, J=9.4, 1.7 Hz, 1H), 6.63 (dd, J=7.5, 2.1 Hz, 1H), 5.28 (s,2H), 4.53 (d, J=5.7 Hz, 2H), 2.89 (t, J=7.3 Hz, 2H), 2.43 (t, J=7.3 Hz,2H), 1.95-1.88 (s, 1H), 0.96-0.85 (m, 2H), 0.68-0.64 (m, 2H).

Example 74

Synthesis of 1-(7-bromoimidazo[1,5-a]pyridin-1-yl)ethan-1-ol

To a solution of 7-bromoimidazo[1,5-a] pyridine-1-carbaldehyde (550 mg,2.46 mmol) in THF (10 mL) was added methylmagnesium bromide (4.1 mL,12.3 mmol) at −60° C. The mixture was stirred at −60° C. for 2 h. LCMSconfirmed the starting material consumed completely. Saturated ammoniumchloride solution (30 mL) was added and the mixture was extracted withethyl acetate (20 mL×3). The combined organic layers were washed withsaturated salt H₂O and concentrated. The residue was purified by flashcolumn chromatography (ethyl acetate/petroleum ether from 0 to 20%) togive 1-(7-bromoimidazo[1,5-a]pyridin-1-yl)ethan-1-ol (300 mg, yield:51%) as a brown oil. ESI-MS [M+H]⁺: 241.0.

Synthesis of 1-(7-bromoimidazo[1,5-a]pyridin-1-yl)ethan-1-one

To the solution of 1-(7-bromoimidazo[1,5-a]pyridin-1-yl)ethan-1-ol (290mg, 1.2 mL) in DCM (10 mL) was added Dess-Martin (1.0 g, 2.4 mmol) at 0°C., Then the reaction mixture was warmed to RT and stirred for 2 h.Saturated sodium bicarbonate solution (40 mL) was added and the mixturewas extracted with DCM (30 mL×3). The combined organic layers werewashed with saturated salt H₂O and concentrated. The residue waspurified by flash column chromatography (ethyl acetate/petroleum etherfrom 0 to 15%) to give 1-(7-bromoimidazo[1,5-a]pyridin-1-yl)ethan-1-one(150 mg, yield: 52%) as a brown solid. ESI-MS [M+H]⁺: 239.0.

Synthesis ofN-(1-(7-bromoimidazo[1,5-a]pyridin-1-yl)ethyl)-2-methylpropane-2-sulfinamide

To the mixture of 1-(7-bromoimidazo[1,5-a]pyridin-1-yl)ethan-1-one (150mg, 0.63 mmol) and 2-methylpropane-2-sulfinamide (92 mg, 0.76 mmol) inTHF (5 mL) was added tetraethyl titanate (429 mg, 1.90 mmol). Themixture was stirred at 80° C. for 18 h and cooled to RT. Sodiumborohydride (120 mg, 3.15 mmol) was added and the mixture was stirred atRT for 2 h. Saturated ammonium chloride solution (30 mL) was added andthe mixture was extracted with ethyl acetate (30 mL×3). The combinedorganic layers were concentrated and purified by flash columnchromatography (ethyl acetate/petroleum ether from 0 to 15%) to giveN-(1-(7-bromoimidazo[1,5-a]pyridin-1-yl)ethyl)-2-methylpropane-2-sulfinamide(40 mg, yield: 18.5%) as a brown oil. ESI-MS [M+H]⁺: 344.0.

Synthesis of 1-(7-bromoimidazo[1,5-a]pyridin-1-yl)ethan-1-aminehydrochloride

A mixture ofN-(1-(7-bromoimidazo[1,5-a]pyridin-1-yl)ethyl)-2-methylpropane-2-sulfinamide(40 mg, 0.12 mmol) in HCl/MeOH (5 mL, 4 M) was stirred at RT for 2 h andconcentrated to give 1-(7-bromoimidazo[1,5-a]pyridin-1-yl)ethan-1-aminehydrochloride (30 mg, yield: 94%) which was used in the next stepdirectly. ESI-MS [M+H]⁺: 240.0

Synthesis ofN-(1-(7-bromoimidazo[1,5-a]pyridin-1-yl)ethyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(I-74)

To the solution of 1-(7-bromoimidazo[1,5-a]pyridin-1-yl)ethan-1-aminehydrochloride (30 mg, crude) and1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylicacid (20 mg, 0.042 mmol) in dry DMF (3 mL) was added HATU (24 mg, 0.63mmol) and DIPEA (16 mg, 0.125 mmol) at RT. The reaction was stirred atRT for 18 h. Water (30 mL) was added and the mixture was extracted withethyl acetate (30 mL×3). The combined organic layers were washed withbrine, dried over anhydrous sodium sulfate and concentrated. The residuewas purified by prep-HPLC to giveN-(1-(7-bromoimidazo[1,5-a]pyridin-1-yl)ethyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(4.4 mg, yield: 21%) as a white solid. ESI-MS [M+H]⁺: 504.1. Purity:98.49%. ¹H NMR (400 MHz, DMSO): δ 8.41 (d, J=8.0 Hz, 1H), 8.33 (s, 1H),8.31 (s, 1H), 8.27-8.19 (m, 2H), 7.89-7.85 (m, 2H), 7.72 (s, 1H), 7.39(d, J=9.3 Hz, 1H), 7.02-6.97 (m, 1H), 6.72-6.67 (m, 1H), 5.49-5.40 (m,1H), 5.38 (s, 2H), 1.96-1.87 m, 1H), 1.54 (d, J=7.0 Hz, 3H), 0.94-0.88(m, 2H), 0.69-0.63 (m, 2H).

Example 75

Synthesis ofN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(hydroxymethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(I-75)

A solution of ethyl2-((4-(((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-pyrazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-carboxylate(40 mg, 0.074 mmol) in THF (3 mL) was added DIBAL-H (0.5 mL, 1 M) andthe mixture was stirred at RT for 1 h. The reaction was quenched withsaturated NH₄Cl solution (10 mL) and extracted with EtOAc (30 mL×3). Thecombined organic layers were concentrated to give the crude, which waspurified by prep-HPLC to giveN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(hydroxymethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(26.4 mg, 75% yield) as a white solid. ESI-MS [M+H]⁺: 476.2. Purity:100%. ¹H NMR (400 MHz, DMSO): δ 8.58 (t, J=5.6 Hz, 1H), 8.31-8.29 (m,2H), 8.21-8.19 (m, 2H), 7.87 (s, 1H), 7.78 (s, 1H), 7.69 (s, 1H), 7.00(s, 1H), 6.64 (dd, J=7.4, 2.0 Hz, 1H), 5.38 (s, 2H), 5.32 (t, J=3.8 Hz,1H), 4.74 (d, J=3.8 Hz, 2H), 4.55 (d, J=5.7 Hz, 2H), 1.97-1.90 (m, 1H),0.97-0.86 (m, 2H), 0.70-0.60 (m, 2H).

Example 76

Synthesis ofN-((7-bromoimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyrimidin-2-yl)methyl)-1H-pyrazole-4-carboxamide(I-76)

A mixture of 2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyrimidine (40mg, 0.19 mmol),N-((7-bromoimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide(61 mg, 0.19 mmol), Cs₂CO₃ (248 mg, 0.76 mmol) in DMF (2 mL) was stirredat RT for 2 h. Then the reaction mixture was diluted with H₂O (30 mL)and extracted with EtOAc (30 mL×3). The combined organic layers weredried over Na₂SO₄, concentrated and purified by column chromatography(PE/EA=10/1) to give the desired compound N-((7-bromoimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyrimidin-2-yl)methyl)-1H-pyrazole-4-carboxamide(25 mg, yield: 27%) as a white solid. ESI-MS [M+H]⁺: 491.1. Purity:96.39%. ¹H NMR (400 MHz, DMSO): δ 8.69 (d, J=2.4 Hz, 1H), 8.59 (t, J=5.7Hz, 1H), 8.41 (d, J=2.5 Hz, 1H), 8.32 (s, 1H), 8.27-8.20 (m 2H), 7.95(d, J=0.9 Hz, 1H), 7.87 (s, 1H), 7.63 (s, 1H), 6.75-6.69 (m, 1H), 5.43(s, 2H), 4.55 (d, J=5.7 Hz, 2H), 2.02-1.93 (m, 1H), 1.02-0.92 (m, 2H),0.79-0.70 (m, 2H).

Example 77

Synthesis of Ethyl 5-aminoimidazo[1,2-a]pyridine-2-carboxylate

A mixture of pyridine-2,6-diamine (1.09 g, 10 mmol), ethyl3-bromo-2-oxopropanoate (1.62 g, 8.3 mmol) in DMF (10 mL) was stirred at90° C. for 3 h. The mixture was concentrated to give crude ethyl5-aminoimidazo[1,2-a]pyridine-2-carboxylate (2.7 g, yield: 100%) as ablack solid, which was used in the next step without furtherpurification. ESI-MS [M+H]⁺: 206.2.

Synthesis of Ethyl(E)-5-(((dimethylamino)methylene)amino)imidazo[1,2-a]pyridine-2-carboxylate

A mixture of ethyl 5-aminoimidazo[1,2-a]pyridine-2-carboxylate (1.7 g,crude) and DMF-DMA (5 mL) in DMF (5 mL) was stirred at 50° C. for 3 h.The mixture was diluted with H₂O (50 mL), extracted with EtOAc (50mL×3). The combined organic layers were washed with brine, dried overNa₂SO₄ and concentrated in vacuo to give the crude, which was purifiedby silica gel chromatography (MeOH/DCM=1/10) to give ethyl(E)-5-(((dimethylamino)methylene)amino)imidazo[1,2-a]pyridine-2-carboxylate(307 mg, yield: 14%) as a white solid. ESI-MS [M+H]⁺: 261.2.

Synthesis of (5-(methylamino)imidazo[1,2-a]pyridin-2-yl)methanol

A mixture of ethyl(E)-5-(((dimethylamino)methylene)amino)imidazo[1,2-a]pyridine-2-carboxylate(217 mg, 0.83 mmol) and NaBH₄ (314 mg, 8.3 mmol) in THF (10 mL) wasstirred at 60° C. overnight. The mixture was then quenched with 1 M HClsolution and filtered. The filtrate was concentrated to get a crude,which was purified by prep-TLC (MeOH/DCM=1/3) to give(5-(methylamino)imidazo[1,2-a]pyridin-2-yl)methanol (52 mg, yield: 35%)as a white solid. ESI-MS [M+H]⁺: 178.2.

Synthesis of (5-(methylamino)imidazo[1,2-a]pyridin-2-yl)methylmethanesulfonate

To a solution of (5-(methylamino)imidazo[1,2-a]pyridin-2-yl)methanol (32mg, 0.18 mmol) and DIPEA (70 mg, 0.54 mmol) in THF (10 mL) was addedmethanesulfonyl chloride (50.4 mg, 2.4 mmol). The mixture was stirred atRT for 3 h. Water (50 mL) was added and extracted with EtOAc (50 mL×3).The combined organic layers were concentrated to give the(5-(methylamino)imidazo[1,2-a]pyridin-2-yl)methyl methanesulfonate,which was used into the next step without further purification. ESI-MS[M+H]⁺: 256.2.

Synthesis ofN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((5-(methylamino)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(I-77)

A mixture of (5-(methylamino)imidazo[1,2-a]pyridin-2-yl)methylmethanesulfonate (45.9 mg, crude),N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide(50 mg, 0.18 mmol), and Cs₂CO₃ (596 mg, 1.8 mmol) in DMF (5 mL) wasstirred at 50° C. for 3 h. Water (30 mL) was added to the reaction andextracted with EtOAc (50 mL×3). The combined organic layers were washedwith brine, dried over Na₂SO₄ and concentrated in vacuo to give thecrude, which was purified by prep-HPLC (DCM/MeOH=10/1) to giveN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((5-(methylamino)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(5.2 mg, yield: 6.6%) as a white solid. ESI-MS [M+H]⁺: 435.2. Purity:96.21%. ¹H NMR (400 MHz, DMSO): δ 8.59 (t, J=5.6 Hz, 1H), 8.31-8.29 (m,2H), 8.22 (s, 1H), 7.87 (s, 1H), 7.79-7.78 (m, 1H), 7.70 (s, 1H),7.20-7.16 (m, 1H), 6.80-6.77 (m, 2H), 6.64 (dd, J=7.4, 2.1 Hz, 1H), 5.80(d, J=7.4 Hz, 1H), 5.40 (s, 2H), 4.55 (d, J=5.7 Hz, 2H), 2.86 (d, J=4.6Hz, 3H).

Example 78

Synthesis of Methyl(Z)-2-(cyclopropanecarbonyl)-3-(dimethylamino)acrylate

To a mixture of 3-cyclopropyl-3-oxo-propionic acid methyl ester (5 g, 35mmol) in yoluene (20 mL) was added DMF-DMA (8 mL, 36.75 mmol). Theresulting reaction was heated at 110° C. for 16 h. After cooled to RT,the mixture was concentrated to give crude2-cyclopropanecarbonyl-3-dimethylamino-acrylic acid methyl ester (5.3 g,yield: 77%) as a white solid, which was used in the next step withoutfurther purification. ESI-MS [M+H]⁺: 198.1.

Synthesis of Methyl 3-cyclopropyl-1H-pyrazole-4-carboxylate

To a solution of methyl(Z)-2-(cyclopropanecarbonyl)-3-(dimethylamino)acrylate (5.3 g, 27 mmol)in EtOH (20 mL) was added hydrazine hydrate (4 mL) dropwise. Thereaction mixture was stirred at 70° C. for 16 h under N₂ atmosphere. Thereaction mixture was concentrated to give the residue, which waspurified by silica gel column chromatography (petroleum ether/ethylacetate=5/1) to give methyl 3-cyclopropyl-1H-pyrazole-4-carboxylate (2.9g, yield 65%) as a white solid. ESI-MS [M+H]⁺: 167.1.

Synthesis of Methyl3-cyclopropyl-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate

To a solution of methyl 3-cyclopropyl-1H-pyrazole-4-carboxylate (200 mg,1.20 mmol) in dry DMF (5 mL) was added2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine (248 mg, 1.20 mmol)and Cs₂CO₃ (1.17 g, 3.6 mmol). Then the reaction mixture was stirred at55° C. for 16 h under N₂ atmosphere. After cooling to RT, the reactionwas diluted with H₂O (50 mL), extracted with ethyl acetate (50 mL×3).The combined organic layers were washed with brine (20 mL), dried overanhydrous Na₂SO₄ and concentrated in vacuo to give the residue, whichwas purified by silica gel column chromatography (DCM/methanol=10/1) togive methyl3-cyclopropyl-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate(390 mg, yield 96%) as a white solid. ESI-MS [M+H]⁺: 337.4.

Synthesis of3-cyclopropyl-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylicAcid

To a solution of methyl3-cyclopropyl-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate(300 mg, 0.89 mmol) in methanol (5 mL) and H₂O (5 mL) was added LiOH H₂O(187 mg, 4.45 mmol). The resulting reaction was stirred at 50° C. for 16h. Most of the solvent was removed and the residue was diluted with H₂O(10 mL), the pH value of mixture was adjusted to 4-5 by adding HCl (1M). The precipitate was collected and dried to give3-cyclopropyl-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylicacid (230 mg yield 80%) as a white solid. ESI-MS [M+H]⁺: 323.1.

Synthesis ofN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-3-cyclopropyl-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(I-78)

To a solution of3-cyclopropyl-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylicacid (110 mg, 0.34 mmol) in dry DMF (3 mL) was added(7-chloroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride (148 mg,0.68 mmol), HATU (194 mg, 0.51 mmol) and DIPEA (132 mg, 1.02 mmol). Thereaction mixture was stirred at RT for 16 h. The reaction mixture wasdiluted with H₂O (20 mL) and extracted with EtOAc (30 mL×3). Thecombined organic layers were washed with brine (20 mL×2), dried overanhydrous Na₂SO₄ and concentrated in vacuo to give a residue, which waspurified by prep-TLC (DCM/MeOH=10/1) to afford N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-3-cyclopropyl-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(47 mg, yield: 29%) as a white solid. ESI-MS [M+H]⁺: 486.2. Purity:100%. ¹H NMR (400 MHz, DMSO-d6): δ 8.34-8.29 (m, 4H), 8.07 (s, 1H),7.83-7.72 (m, 1H), 7.70 (s, 1H), 7.39 (d, J=9.3 Hz, 1H), 6.99 (dd,J=9.4, 1.7 Hz, 1H), 6.64 (dd, J=7.5, 2.1 Hz, 1H), 5.24 (s, 2H), 4.53 (d,J=5.7 Hz, 2H), 2.71-2.60 (m, 1H), 1.97-1.86 (m, 1H), 0.95-0.88 (m, 2H),0.85-0.79 (m, 2H), 0.76-0.72 (m, 2H), 0.68-0.64 (m, 2H).

Example 79

N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-5-ethynylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(I-79)

To a solution of2-(chloromethyl)-6-cyclopropyl-5-((trimethylsilyl)ethynyl)imidazo[1,2-a]pyridine(30 mg, 0.1 mmol) andN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide(27.5 mg, 0.1 mmol) in DMF (4 mL) was added Cs₂CO₃ (174 mg, 0.8 mmol).The reaction was stirred at RT for 4 h. The reaction mixture wasconcentrated to give the crude which was purified by prep-HPLC to giveN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-5-ethynylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(7.7 mg, yield: 16.7%) as a pale solid. ESI-MS [M+H]⁺: 470.1. Purity:100%. ¹H NMR (400 MHz, DMSO) 8.58 (t, J=5.7 Hz, 1H), 8.33-8.27 (m, 2H),8.22 (s, 1H), 7.90 (s, 1H), 7.86 (s, 1H), 7.80-7.74 (m, 1H), 7.54 (d,J=9.4 Hz, 1H), 6.81 (d, J=9.5 Hz, 1H), 6.67-6.62 (m, 1H), 5.46-5.42 (m,3H), 4.55 (d, J=5.7 Hz, 2H), 2.30-2.22 (m, 1H), 1.12-1.01 (m, 2H),0.85-0.75 (m, 2H).

Example 80

Synthesis of 5-cyclopropylpyridin-2-amine

A mixture of 5-bromopyridin-2-amine (100 g, 585 mmol),cyclopropylboronic acid (60 g, 701 mmol), Pd(AcO)₂ (6.5 g, 29 mmol),SPhos (24 g, 58.5 mmol) and K₃PO₄ (372 g, 1.755 mol) in toluene/H₂O (1.2L/0.12 L) was stirred at 90° C. for 14 h under N₂. The reaction wasconcentrated in vacuo to give the crude, which was purified with silicagel chromatography (PE/EA=1/2) to give the 5-cyclopropylpyridin-2-amine(61 g, yield: 78%) as a yellow solid. ESI-MS [M+H]⁺: 135.1.

Synthesis of 2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine

A mixture of 5-cyclopropylpyridin-2-amine (61 g, 455 mmol) and1,3-dichloropropan-2-one (172 g, 1365 mmol) in EtOH (1 L) was stirred at95° C. for 13 h. The reaction was concentrated to remove the EtOH. ThepH of the residue was adjusted to 9 by addition of aqueous NaHCO₃ andextracted with EtOAc (1 L×3). The combined organic layers were washedwith brine, dried over Na₂SO₄ and concentrated in vacuo to give thecrude, which was purified with silica gel chromatography (EA) to givethe 2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine (40 g, yield:42%) as a yellow solid. ESI-MS [M+H]⁺: 207.1.

Synthesis of 2-(azidomethyl)-6-cyclopropylimidazo[1,2-a]pyridine

To a solution of 2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine(40 g, 193 mmol) in DMF (600 mL) was added NaN₃ (18.8 g, 290 mmol). Theresulting reaction was stirred at RT for 2 h. The reaction was dilutedwith H₂O (500 mL) and extracted with EtOAc (500 mL×3). The combinedorganic layers were washed with brine, dried over Na₂SO₄ andconcentrated in vacuo to give the crude, which was purified with silicagel chromatography (PE/EA=2/1) to give the2-(azidomethyl)-6-cyclopropylimidazo[1,2-a]pyridine (35 g, yield: 85%)as a yellow solid. ESI-MS [M+H]⁺: 214.1.

Synthesis of Ethyl1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate

A mixture of 2-(azidomethyl)-6-cyclopropylimidazo[1,2-a]pyridine (35 g,163.5 mmol), ethyl propiolate (17.6 g, 180 mmol), CuSO₄ (2.6 g, 16.35mmol) and sodium ascorbate (3.3 g, 16.35 mmol) in H₂O/t-BuOH (150 mL/150mL) was stirred at RT for 3 h. Yellow solid was precipitated after 3 hand the mixture was filtered. The cake was dried to give the ethyl1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(29 g, yield: 57%) as a yellow solid, which was used in the next stepwithout further purification. ESI-MS [M+H]⁺: 312.1.

Synthesis of1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicAcid

A mixture of ethyl1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(29 g, 93.2 mmol) and LiOH (6.7 g, 279.6 mmol, solution in 50 mL H₂O) inTHF/EtOH (150 mL/150 mL) was stirred at 50° C. for 2 h. The reaction wasconcentrated to remove most of the solvent. The pH of the residue wasadjusted to 4 by 2N HCl and a pink solid was precipitated out. Themixture was filtered and the filter cake was dried to give1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (20 g, 77%) as a pink solid. ESI-MS [M+H]⁺: 284.1.

Synthesis ofN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(I-80)

To a solution of1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (10 g, 35.3 mmol), (7-chloroimidazo[1,5-a]pyridin-1-yl)methanaminehydrochloride (9.2 g, 42.4 mmol), HOBT (6.67 g, 49.42 mmol) and EDCI(9.5 g, 49.42 mmol) in DMF (500 mL) was added DIPEA (31.3 mL, 176.5mmol). The resulting mixture was stirred at RT for 14 h. The reactionwas poured into H₂O (1 L) and yellow solid was precipitated out. Themixture was filtered and the cake was dried to give the crude, which waspurified with silica gel chromatography (DCM/MeOH=10/1) to give theN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(7.2 g, yield: 45.9%) as a white solid. HPLC Purity: 99.09% (214 nm),99.18% (254 nm). LCMS m/z: 447.1 [M+H]*, t_(R)=1.098 (min). ¹H NMR (400MHz, DMSO): δ 8.91 (t, J=5.8 Hz, 1H), 8.56 (s, 1H), 8.34 (s, 1H),8.31-8.29 (m, 2H), 7.84-7.82 (m, 2H), 7.40 (d, J=9.3 Hz, 1H), 7.01 (dd,J=9.4, 1.7 Hz, 1H), 6.64 (dd, J=7.5, 2.1 Hz, 1H), 5.72 (s, 2H), 4.62 (d,J=5.9 Hz, 2H), 1.95-1.89 (m, 1H), 0.94-0.89 (m, 2H), 0.69-0.65 (m, 2H).

Example 81

Synthesis ofN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((8-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide

To a solution ofN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(hydroxymethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(80 mg, 0.17 mmol) in DCM (5 mL) was added SOCl₂ (0.5 mL, 1.7 mmol)slowly at 0° C. The resulting mixture was stirred at RT for 2 h. Thereaction was concentrated in vacuo to give the crude, which was purifiedby silica gel chromatography (EtOAc/PE=2/1) to give methyl2-(2-((4-(((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-pyrazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)acetate(20 mg, yield: 24%) as a white solid. ESI-MS [M+H]⁺: 494.2.

Synthesis of Methyl2-(2-((4-(((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-pyrazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)acetate(I-81)

A mixture methyl2-(2-((4-(((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-pyrazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)acetate(40 mg, 0.08 mmol), Pd(dppf)₂Cl₂ (20 mg, 0.016 mmol), TEA (0.5 mL, 0.4mmol) in MeOH (15 mL) was stirred at 55° C. for 3 h under CO atmosphere.The reaction was monitored by LCMS until the starting material consumed.The reaction was concentrated in vacuo to give the crude, which waspurified by prep-HPLC to give methyl2-(2-((4-(((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-pyrazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)acetate(22.7 mg, 55% yield) as a white solid. ESI-MS [M+H]⁺: 518.1. Purity:95.6%. ¹H NMR (400 MHz, DMSO): δ 8.58 (t, J=5.7 Hz, 1H), 8.34-8.28 (m,2H), 8.25 (d, J=1.3 Hz, 1H), 8.18 (s, 1H), 7.87 (s, 1H), 7.80-7.74 (m,1H), 7.66 (s, 1H), 6.94 (d, J=1.2 Hz, 1H), 6.64 (dd, J=7.4, 2.1 Hz, 1H),5.38 (s, 2H), 4.55 (d, J=5.7 Hz, 2H), 3.89 (s, 2H), 3.57 (s, 3H),1.94-1.87 (m, 1H), 0.94-0.89 (m, 2H), 0.69-0.60 (m, 2H).

Example 82

Synthesis of 1-benzyl 6-methyl 3-oxohexanedioate

To a solution of benzyl acetate (1.5 g, 10 mmol) in THF (10 mL) wasadded LDA (1 M, 15 mmol) at −78° C. and stirred for 1 h (solution A). Toa solution of 4-methoxy-4-oxobutanoic acid (1.58 g, 12 mmol) in THF (10mL) was added CDI (1.94 g, 12 mmol) and stirred at RT for 30 min(solution B). Solution B was added to solution A at −78° C. and stirredfor another 2 h. Saturated NH₄Cl (100 mL) was added to quenched thereaction and the reaction mixture was extracted with EtOAc (100 mL×3).The combined organics were concentrated and purified by silica gelchromatography (EA/PE=1/10) to give 1-benzyl 6-methyl 3-oxohexanedioate(500 mg, yield: 19%) as a colorless oil. ESI-MS [M+H]⁺: 265.1.

Synthesis of 1-benzyl 6-methyl(E)-2-((dimethylamino)methylene)-3-oxohexanedioate

A solution of 1-benzyl 6-methyl 3-oxohexanedioate (490 mg, 1.86 mmol) inDMF-DMA (443 mg, 3.72 mmol) was heated to 80° C. for 2 h and thenconcentrated to give 1-benzyl 6-methyl(E)-2-((dimethylamino)methylene)-3-oxohexanedioate (600 mg, crude) as ayellow oil which was used in the next step without purification. ESI-MS[M+H]⁺: 320.1.

Synthesis of benzyl 3-(3-methoxy-3-oxopropyl)-1H-pyrazole-4-carboxylate

To a solution of 1-benzyl 6-methyl(E)-2-((dimethylamino)methylene)-3-oxohexanedioate (600 mg, 1.86 mmol)in MeOH (6 mL) was added hydrazine hydrochloride (255 mg, 3.72 mmol).The mixture was stirred at RT for 16 h. The reaction was concentrated togive the crude, which was purified by silica gel chromatography(EA/PE=1/1) to give benzyl3-(3-methoxy-3-oxopropyl)-1H-pyrazole-4-carboxylate (384 mg, yield: 64%for two steps) as a yellow oil. ESI-MS [M+H]⁺: 289.1.

Synthesis of benzyl1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-5-(3-methoxy-3-oxopropyl)-1H-pyrazole-4-carboxylate

To a solution of benzyl3-(3-methoxy-3-oxopropyl)-1H-pyrazole-4-carboxylate (90 mg, 0.31 mmol)and 2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine (78 mg, 0.38mmol) in DMF (5 mL) was added Cs₂CO₃ (302 mg, 0.93 mmol) at RT. Themixture was stirred at RT for 16 h. The reaction was quenched with H₂O(10 mL) and extracted with ethyl acetate (3×50 mL). The organic layerswere washed with brine, dried over Na₂SO₄, and the solvent is evaporatedunder reduced pressure to give a residue which was purified by prep-TLC(MeOH/DCM=1/15) to give benzyl1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-5-(3-methoxy-3-oxopropyl)-1H-pyrazole-4-carboxylate(30 mg, yield: 20%) as yellow oil. ESI-MS [M+H]⁺: 459.1.

Synthesis of1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-5-(3-methoxy-3-oxopropyl)-1H-pyrazole-4-carboxylicAcid

To a solution of benzyl1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-5-(3-methoxy-3-oxopropyl)-1H-pyrazole-4-carboxylate(100 mg, 0.22 mmol) in MeOH (10 mL) was added Pd/C (10%, 30 mg). Themixture was stirred at RT for 3 h under H₂. The reaction was filtratedand concentrated to give1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-5-(3-methoxy-3-oxopropyl)-1H-pyrazole-4-carboxylicacid (67 mg, 83%) as a white solid. ESI-MS [M+H]⁺: 369.1.

Synthesis of Methyl3-(4-(((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazol-5-yl)propanoate(I-82)

To a solution of1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-5-(3-methoxy-3-oxopropyl)-1H-pyrazole-4-carboxylicacid (80 mg, 0.22 mmol) and(7-chloroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride (48 mg,0.26 mmol) in dry DMF (4 mL) was added HATU (125 mg, 0.33 mmol) andDIPEA (114 mg, 0.88 mmol) at RT. The reaction was stirred for 3 h. Water(30 mL) was added and the mixture was extracted with EtOAc (50 mL×3).The organic layers were washed with brine (80 mL), dried over Na₂SO₄ andconcentrated in vacuo to give the crude, which was purified by prep-HPLC(DCM/MeOH=10/1) to give methyl3-(4-(((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazol-5-yl)propanoate(15.4 mg, yield: 13%) as a yellow solid. ESI-MS [M+H]⁺: 532.2. Purity:98.7%. ¹H NMR (400 MHz, DMSO): δ 8.70-8.54 (m, 2H), 8.48 (s, 1H), 8.34(dd, J=7.5, 0.8 Hz, 1H), 8.04-8.01 (m, 2H), 7.87-7.79 (m, 1H), 7.74 (d,J=9.3 Hz, 1H), 7.62 (d, J=9.0 Hz, 1H), 6.72 (dd, J=7.5, 2.1 Hz, 1H),5.66 (s, 2H), 4.61 (d, J=5.7 Hz, 2H), 3.58 (s, 3H), 3.33-3.24 (m, 2H),2.69-2.59 (m, 2H), 2.13-1.97 (m, 1H), 1.09-0.97 (m, 2H), 0.81-0.69 (m,2H).

Example 83

Synthesis of N-((4-bromopyridin-2-yl)methyl)-2,2-difluoroacetamide

To a mixture of (4-bromopyridin-2-yl)methanamine (500 mg, 2.67 mmol),DIPEA (1.7 g, 13.4 mmol) and 2,2-difluoroacetic acid (256 mg, 2.67 mmol)in DMF (10 mL) was added HATU (2.0 g, 5.34 mmol). The mixture wasstirred at RT for 3 h. Water (100 mL) was added and the mixture wasextracted with EtOAc (100 mL×3). The combined organics were washed withbrine, dried over Na₂SO₄ and concentrated to give the crude, which waspurified by silica gel chromatography (EA/PE=1/2) to giveN-((4-bromopyridin-2-yl)methyl)-2,2-difluoroacetamide (400 mg, yield:56%) as a yellow oil. ESI-MS [M+H]⁺: 265.0

Synthesis of 7-bromo-3-(difluoromethyl)imidazo[1,5-a]pyridine

To a solution of N-((4-bromopyridin-2-yl)methyl)-2,2-difluoroacetamide(400 mg, 1.5 mmol) in CH₃CN (10 mL) was added POBr₃ (2.2 g, 7.5 mmol),The mixture was heated to reflux for 3 h. After cooled to RT, H₂O (50mL) was added and extracted with EtOAc (50 mL×4). The organic layerswere dried over Na₂SO₄ and concentrated to give the crude, which waspurified by silica gel chromatography (EA/PE=1/2) to give7-bromo-3-(difluoromethyl)imidazo[1,5-a]pyridine (180 mg, yield: 49%) asa yellow oil. ESI-MS [M+H]2:6247.0.

Synthesis of7-bromo-3-(difluoromethyl)imidazo[1,5-a]pyridine-1-carbaldehyde

To a solution of 7-bromo-3-(difluoromethyl)imidazo[1,5-a]pyridine (180mg, 0.73 mmol) in DMF (3 mL) was added POCl₃ (223 m, 1.46 mmol). Themixture was stirred at 100° C. for 1 h. After cooled to RT, H₂O (30 mL)was added and extracted with EtOAc (50 mL×3). The organic phase wasdried over Na₂SO₄, concentrated and purified by silica gelchromatography (EA/PE=1/2) to give7-bromo-3-(difluoromethyl)imidazo[1,5-a]pyridine-1-carbaldehyde (100 mg,yield: 50%) as a yellow oil. ESI-MS [M+H]⁺: 275.0.

Synthesis ofN-((7-bromo-3-(difluoromethyl)imidazo[1,5-a]pyridin-1-yl)methyl)-2-methylpropane-2-sulfinamide

To a solution of7-bromo-3-(difluoromethyl)imidazo[1,5-a]pyridine-1-carbaldehyde (100 mg,0.36 mmol) and 2-methylpropane-2-sulfinamide (65 mg, 0.54 mmol) in THF(5 mL) was added Ti(Oi-Pi)₄ (305 mg, 1.08 mmol). The mixture wasrefluxed for 3 h. After cooled to RT, NaBH₄ (69 mg, 1.8 mmol) was added.The mixture was stirred at RT for 5 h. The reaction was then quenchedwith H₂O (20 mL) and the mixture was extracted with ethyl acetate (3×50mL). The combined organic layers were washed with brine, dried overNa₂SO₄ and concentrated in vacuo to give the residue, which was purifiedby prep-TLC (MeOH/DCM=1/25) to giveN-((7-bromo-3-(difluoromethyl)imidazo[1,5-a]pyridin-1-yl)methyl)-2-methylpropane-2-sulfinamide(100 mg, yield: 73%) as a yellow oil. ESI-MS [M+H]⁺: 380.0.

Synthesis of(7-bromo-3-(difluoromethyl)imidazo[1,5-a]pyridin-1-yl)methanamine

A mixture ofN-((7-bromo-3-(difluoromethyl)imidazo[1,5-a]pyridin-1-yl)methyl)-2-methylpropane-2-sulfinamide(100 mg, 0.26 mmol) in HCl (4 M solution in MeOH, 5 mL) was stirred atRT for 1 h. The reaction was concentrated to give(7-bromo-3-(difluoromethyl)imidazo[1,5-a]pyridin-1-yl)methanamine (60mg, 83%) as a white solid, which was used in the next step withoutfurther purification. ESI-MS [M+H]⁺: 276.0.

Synthesis ofN-((7-bromo-3-(difluoromethyl)imidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(I-83)

To a solution of(7-bromo-3-(difluoromethyl)imidazo[1,5-a]pyridin-1-yl)methanamine (40mg, 0.15 mmol) and1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylicacid (49 mg, 0.17 mmol) in dry DMF (3 mL) was added HATU (83 mg, 0.22mmol) and DIPEA (75 mg, 0.58 mmol) at RT. The reaction was stirred at RTfor 5 h. Water (20 mL) was added and the mixture was extracted withEtOAc (25 mL×3). The organic layers were washed with brine (50 mL),dried over Na₂SO₄ and concentrated under reduced pressure to give thecrude product, which was purified by prep-HPLC (DCM/MeOH=10/1) to giveN-((7-bromo-3-(difluoromethyl)imidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(6 mg, yield: 8%) as a yellow solid. ESI-MS [M+H]⁺: 540.1. Purity:71.3%. ¹H NMR (400 MHz, DMSO): δ 8.68 (t, J=5.5 Hz, 1H), 8.46 (s, 1H),8.33 (d, J=7.4 Hz, 1H), 8.25 (s, 1H), 8.18 (s, 1H), 7.90-7.87 (m, 2H),7.61-7.48 (m, 2H), 7.25 (d, J=8.7 Hz, 1H), 7.00 (dd, J=7.5, 1.8 Hz, 1H),5.49 (s, 2H), 4.59 (d, J=5.6 Hz, 2H), 1.99-1.94 (m, 1H), 1.06-0.86 (m,2H), 0.72-0.69 (m, 2H).

Example 84

Synthesis of 6-chloro-1H-pyrrolo[3,2-b]pyridine-2-carboxylic Acid

A mixture of 2,5-dichloropyridin-3-amine (2.0 g, 12.27 mmol),2-oxopropanoic acid (3.24 g, 36.81 mmol), Pd(OAc)₂ (551 mg, 2.45 mmol),PPh₃ (2.57 g, 9.82 mmol) and Et₃N (4.97 g, 49.08 mmol) in DMF (30 mL)was stirred at 100° C. for 16 h. The reaction mixture was concentratedto give a crude which was purified by silica gel chromatography(DCM/MeOH=5/1) to give 6-chloro-1H-pyrrolo[3,2-b]pyridine-2-carboxylicacid (2.41 g, yield: 100%) as a yellow solid. ESI-MS [M+H]⁺: 197.0.

Synthesis of Methyl 6-chloro-1H-pyrrolo[3,2-b]pyridine-2-carboxylate

To a stirred solution of 6-chloro-1H-pyrrolo[3,2-b]pyridine-2-carboxylicacid (2.41 g, 12.27 mmol) in MeOH (80 mL) was added SOCl₂ (4.38 g, 36.81mmol) at RT. The mixture was stirred at 80° C. for 5 h. The reactionmixture was concentrated to give the residue, which was dissolved inEtOAc (100 mL) and washed with NaHCO₃ (100 mL) and brine (100 mL), driedover Na₂SO₄, concentrated and purified by silica gel chromatography(EA/PE=1/5) to give methyl6-chloro-1H-pyrrolo[3,2-b]pyridine-2-carboxylate (1.0 g, yield: 39%) asa yellow solid. ESI-MS [M+H]⁺: 211.1.

Synthesis of Methyl6-chloro-1-tosyl-1H-pyrrolo[3,2-b]pyridine-2-carboxylate

To a stirred solution of NaH (42 mg, 1.04 mmol) in THF (4 mL) was addedthe solution of 6-chloro-1H-pyrrolo[3,2-b]pyridine-2-carboxylate (200mg, 0.95 mmol) in THF (1 mL) at 0° C. After stirring for 20 min, asolution of TsCl (199 mg, 1.04 mmol) in THF (1 mL) was added thereto at0° C. The resulting mixture was stirred at 0° C. for another 2 h. Thereaction mixture was quenched with 1 M HCl, diluted with H₂O (20 mL) andextracted with EtOAc (25 mL×3). The combined organics were washed withNaHCO₃ (20 mL), brine (80 mL), dried over Na₂SO₄, concentrated andpurified by silica gel chromatography (EA/PE=1/5) to give methyl6-chloro-1-tosyl-1H-pyrrolo[3,2-b]pyridine-2-carboxylate (240 mg, yield:69%) as a yellow solid. ESI-MS [M+H]⁺: 365.1.

Synthesis of Methyl6-cyclopropyl-1-tosyl-1H-pyrrolo[3,2-b]pyridine-2-carboxylate

A mixture of methyl6-chloro-1-tosyl-1H-pyrrolo[3,2-b]pyridine-2-carboxylate (240 mg, 0.658mmol), cyclopropylboronic acid (170 mg, 1.97 mmol), Pd(OAc)₂ (15 mg,0.0658 mmol), tricyclohexyl phosphine (37 mg, 0.132 mmol) and K₃PO₄ (489mg, 2.30 mmol) in toluene (10 mL) and H₂O (2 mL) was stirred at 100° C.for 16 h. The reaction mixture was filtered and washed with EtOAc (50mL). The combined filtrate was washed with H₂O (50 mL×1) and brine (50mL×1), dried over Na₂SO₄, concentrated and purified by silica gelchromatography (EA/PE=1/3) to give methyl6-cyclopropyl-1-tosyl-1H-pyrrolo[3,2-b]pyridine-2-carboxylate (180 mg,yield: 74%) as a yellow solid. ESI-MS [M+H]⁺: 371.1.

Synthesis of(6-cyclopropyl-1-tosyl-1H-pyrrolo[3,2-b]pyridin-2-yl)methanol

To a stirred solution of LiAlH₄ (74 mg, 1.94 mmol) in THF (5 mL) wasadded the solution of methyl6-cyclopropyl-1-tosyl-1H-pyrrolo[3,2-b]pyridine-2-carboxylate (180 mg,0.486 mmol) in THF (1 mL) at −78° C. dropwise. The mixture was stirredat −78° C. for 2 h. The reaction mixture was quenched with Na₂SO₄.10H₂Oand filtered. The filtrate was concentrated and dried to give(6-cyclopropyl-1-tosyl-1H-pyrrolo[3,2-b]pyridin-2-yl)methanol (105 mg,yield: 63%) as a yellow solid. ESI-MS [M+H]⁺: 343.1.

Synthesis of2-(chloromethyl)-6-cyclopropyl-1-tosyl-1H-pyrrolo[3,2-b]pyridine

To a stirred solution of(6-cyclopropyl-1-tosyl-1H-pyrrolo[3,2-b]pyridin-2-yl)methanol (105 mg,0.307 mmol) in DCM (10 mL) was added the solution of SOCl₂ (182 mg, 1.53mmol) in DCM (1 mL) at 0° C. dropwise. The mixture was stirred at RT for1 h. The reaction mixture was concentrated to give the residue, whichwas dissolved in EtOAc (40 mL) and washed with NaHCO₃ (40 mL) and brine(40 mL), dried over Na₂SO₄, concentrated and dried in vacuo to give2-(chloromethyl)-6-cyclopropyl-1-tosyl-1H-pyrrolo[3,2-b]pyridine (110mg, yield: 99%) as a yellow syrup. ESI-MS [M+H]⁺: 361.1.

Synthesis ofN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-1-tosyl-1H-pyrrolo[3,2-b]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide

A mixture of2-(chloromethyl)-6-cyclopropyl-1-tosyl-1H-pyrrolo[3,2-b]pyridine (110mg, 0.305 mmol),N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide(70 mg, 0.254 mmol) and Cs₂CO₃ (248 mg, 0.762 mmol) in DMF (5 mL) wasstirred at 50° C. for 2 h. The reaction mixture was poured into H₂O (40mL) and extracted with EtOAc/THF (50 mL×3, 5/1 (v/v)). The combinedorganic layers were washed with brine, dried over Na₂SO₄, concentratedand purified by prep-TLC (DCM/MeOH=10/1) to giveN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-1-tosyl-1H-pyrrolo[3,2-b]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(38 mg, yield: 25%) as a yellow solid. ESI-MS [M+H]⁺: 600.1.

Synthesis ofN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-1H-pyrrolo[3,2-b]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(I-84)

A mixture ofN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-1-tosyl-1H-pyrrolo[3,2-b]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(35 mg, 0.0583 mmol) and LiOH.H₂O (307 mg, 7.30 mmol) in MeOH/H₂O (2mL/0.5 mL) was stirred at RT for 2 h. The reaction was concentrated invacuo to remove the MeOH. And the residue was diluted in H₂O (15 mL) andextracted with EtOAc (30 mL×3). The combined organics were washed withbrine (90 mL), dried over Na₂SO₄, concentrated and purified by prep-TLC(DCM/MeOH=7/1) to giveN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-1H-pyrrolo[3,2-b]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(12 mg, yield: 46%) as a white solid. ESI-MS [M+H]⁺: 446.0. Purity:97.56%. ¹H NMR (400 MHz, DMSO): δ 11.22 (s, 1H), 8.59 (t, J=5.4 Hz, 1H),8.30 (m, 2H), 8.18 (d, J=20.8 Hz, 2H), 7.90 (s, 1H), 7.77 (s, 1H), 7.28(s, 1H), 6.64 (d, J=7.3 Hz, 1H), 6.45 (s, 1H), 5.47 (s, 2H), 4.55 (d,J=5.5 Hz, 2H), 2.01 (m, 1H), 0.96 (m, 2H), 0.68 (m, 2H).

Example 85

Synthesis ofN-((7-bromoimidazo[1,5-a]pyridin-1-yl)methyl)-3-cyclopropyl-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(I-85)

To a solution of3-cyclopropyl-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylicacid (50 mg, 0.16 mmol), in dry DMF (5 mL), was added(7-bromoimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride (54 mg,0.21 mmol), HATU (91 mg, 0.24 mmol) and DIPEA (62 mg, 0.48 mmol). Thereaction mixture was stirred at RT for 16 h. The reaction mixturediluted with H₂O (20 mL) and extracted with ethyl acetate (30 mL×3). Thecombined organic layers were washed with brine (20 mL×2), dried overanhydrous Na₂SO₄ and concentrated in vacuo. The residue was purified byprep-TLC (DCM/MeOH=10:1) to affordN-((7-bromoimidazo[1,5-a]pyridin-1-yl)methyl)-3-cyclopropyl-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(30 mg, yield: 36%) as a white solid. ESI-MS [M+H]⁺: 532.2. Purity:99.12%. ¹H NMR (400 MHz, DMSO-d6): δ 8.33 (m, 3H), 8.24 (d, J=7.4 Hz,1H), 8.07 (s, 1H), 7.94 (d, J=0.8 Hz, 1H), 7.70 (s, 1H), 7.39 (d, J=9.3Hz, 1H), 6.99 (dd, J=9.4, 1.6 Hz, 1H), 6.71 (dd, J=7.4, 1.9 Hz, 1H),5.24 (s, 2H), 4.53 (d, J=5.7 Hz, 2H), 2.67-2.61 (m, 1H), 1.93-1.88 (m,1H), 0.94-0.89 (m, 2H), 0.85-0.80 (m, 2H), 0.75-0.73 (m, 2H), 0.69-0.64(m, 2H).

Example 86

Synthesis of2-(2-((4-(((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-pyrazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)aceticacid (I-86)

To a solution of methyl2-(2-((4-(((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-pyrazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)acetate(50 mg, 0.096 mmol) in EtOH (3 mL) was added NaOH (3 mL, 1 M solution inH₂O). The resulting reaction was stirred at RT for 1 h. HCl (1 M, 3 mL)was added and the reaction was concentrated to give a crude product,which was purified by prep-HPLC to give2-(2-((4-(((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-pyrazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)aceticacid (16.6 mg, 35% yield) as a white solid. ESI-MS [M+H]⁺: 504.1.Purity: 97.1%. ¹H NMR (400 MHz, DMSO): δ 8.64 (t, J=5.6 Hz, 1H),8.30-8.28 (m, 2H), 8.23 (s, 1H), 8.10 (s, 1H), 7.87 (s, 1H), 7.78 (s,1H), 7.61 (s, 1H), 6.84 (s, 1H), 6.63 (dd, J=7.4, 2.0 Hz, 1H), 5.38 (s,2H), 4.55 (d, J=5.7 Hz, 2H), 3.51 (s, 2H), 1.87-1.81 (m, 1H), 0.89-0.83(m, 2H), 0.62-0.56 (m, 2H).

Example 87

Synthesis ofN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(hydroxyethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(I-87)

To the solution of methyl2-(2-((4-(((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-pyrazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)acetate(20 mg, 0.039 mmol) in THF/MeOH (3 mL/1 mL) was added LiBH₄ (4.25 mg,0.195 mmol). The resulting reaction was stirred at RT for 1 h. Thereaction was quenched with H₂O (3 mL) and concentrated in vacuo to givethe crude, which was purified with prep-HPLC to giveN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(hydroxyethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(7.1 mg, 37% yield) as a white solid. ESI-MS [M+H]⁺: 490.2. Purity:99.6%. ¹H NMR (400 MHz, DMSO): δ 8.58 (t, J=5.7 Hz, 1H), 8.34-8.28 (m,2H), 8.20-8.12 (m, 2H), 7.87 (s, 1H), 7.79-7.73 (m, 1H), 7.65 (s, 1H),6.84 (s, 1H), 6.65 (dd, J=7.5, 2.1 Hz, 1H), 5.39 (s, 2H), 4.78 (t, J=5.8Hz, 1H), 4.55 (d, J=5.8 Hz, 2H), 3.74-3.70 (m, 2H), 2.96 (t, J=6.7 Hz,2H), 1.91-1.85 (m, 1H), 0.92-0.79 (m, 2H), 0.67-0.63 (m, 2H).

Example 88 See Example 89 for Synthesis of1-((5-amino-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide(I-88)

Example 89

Synthesis of 3-iodopyridine-2,6-diamine

To a solution of 3-iodopyridine-2,6-diamine (5.0 g, 45.9 mmol) in2-methyltetrahydrofuran (35 mL) was added K₂CO₃ (6.7 g, 48.2 mmol)followed by addition of a solution of I₂ (12.2 g, 48.2 mmol) in2-methyltetrahydrofuran (20 mL) dropwise over 0.5 h. The resultingreaction was stirred at RT for 5 h. Water (100 mL) was added to thereaction and extracted with EtOAc (150 mL×2). The combined organiclayers were concentrated in vacuo to give the crude, which was purifiedby silica gel chromatography (DCM/MeOH=20/1) to give3-iodopyridine-2,6-diamine (8.5 g, yield: 78.7%) as a yellow solid.ESI-MS [M+H]⁺: 236.0.

Synthesis of 3-cyclopropylpyridine-2,6-diamine

To a solution of 3-iodopyridine-2,6-diamine (2.0 g, 8.5 mmol) andcyclopropylboronic acid (2.2 g, 25.5 mmol) in toluene/H₂O (30 mL/3 mL)was added K₃PO₄ (6.3 g, 29.8 mmol), SPhos (1.0 g, 2.6 mmol) and Pd(OAc)₂(0.3 g, 1.3 mmol). The resulting mixture was stirred at 90° C. for 16 hunder N₂ atmosphere. Water (100 mL) was added to the reaction andextracted with EtOAc (100 mL×3). The combined organic layers wereconcentrated and purified by silica gel chromatography (DCM/MeOH=20/1)to give 3-cyclopropylpyridine-2,6-diamine (0.78 g, yield: 61.9%) as ayellow solid. ESI-MS [M+H]⁺: 150.3.

Synthesis of 2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridin-5-amineand 2-(chloromethyl)-8-cyclopropylimidazo[1,2-a]pyridin-5-amine

To a solution of 3-cyclopropylpyridine-2,6-diamine (0.48 g, 3.22 mmol)in DMF (10 mL) was added 1, 3-dichloropropan-2-one (2.04 g, 16.1 mmol).The mixture was stirred at 90° C. for 16 h. Water (50 mL) was added tothe reaction and extracted with EtOAc (50 mL×3). The combined organiclayers were concentrated and purified by silica gel chromatography(DCM/MeOH=20/1) to give mixture of2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridin-5-amine and2-(chloromethyl)-8-cyclopropylimidazo[1,2-a]pyridin-5-amine (0.18 g,yield: 16.4%) as a yellow solid. ESI-MS [M+H]⁺: 222.3.

Synthesis of1-((5-amino-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide(I-88) and1-((5-amino-8-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide(I-89)

To a mixture of2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridin-5-amine and2-(chloromethyl)-8-cyclopropylimidazo[1,2-a]pyridin-5-amine (80 mg, 0.36mmol) andN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide(99 mg, 0.36 mmol) in DMF (4 mL) was added Cs₂CO₃ (234 mg, 0.72 mmol).The mixture was stirred at RT for 8 h. Water (50 mL) was added to thereaction and extracted with EtOAc (50 mL×3). The combined organic layerswere concentrated and purified by prep-HPLC to give1-((5-amino-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide(16.4 mg, yield: 10.0%) as a white solid. ESI-MS [M+H]⁺: 461.2. Purity:99.5% and1-((5-amino-8-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide(4.1 mg, yield: 2.5%) as a white solid. ESI-MS [M+H]⁺: 461.1. Purity:95.3%.1-((5-amino-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide¹H NMR (400 MHz, DMSO): δ 8.58 (t, J=5.6 Hz, 1H), 8.37-8.13 (m, 3H),7.82 (d, J=31.9 Hz, 3H), 6.92 (d, J=9.0 Hz, 1H), 6.74-6.58 (m, 2H), 6.41(s, 2H), 5.36 (s, 2H), 4.55 (d, J=5.7 Hz, 2H), 1.76 (m, 1H), 0.88 (m,2H), 0.51 (t, J=4.7 Hz, 2H).1-((5-amino-8-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide.¹H NMR (400 MHz, DMSO): δ 8.60 (t, J=5.7 Hz, 1H), 8.30 (d, J=7.1 Hz,1H), 8.22 (s, 1H), 7.89 (s, 1H), 7.79 (s, 1H), 7.65 (s, 1H), 6.84-6.59(m, 2H), 6.28 (s, 2H), 5.85 (d, J=7.6 Hz, 1H), 5.42 (s, 2H), 4.55 (d,J=5.7 Hz, 2H), 2.23 (m, 1H), 0.92-0.79 (m, 2H), 0.72 (m, 1H).

Example 90

Synthesis ofN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl-d2)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(I-90)

To a solution of1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylicacid (65 mg, 0.23 mmol),(7-chloroimidazo[1,5-a]pyridin-1-yl)methan-d2-amine hydrochloride (50mg, 0.23 mmol) and HATU (114 mg, 0.3 mmol) in DMF (15 mL) was addedDIPEA (148 mg, 1.15 mmol). The resulting reaction was stirred at RT for12 h. H₂O (25 mL) was added to the reaction and extracted with EtOAc (25mL×3). The combined organic layers were washed with brine, dried overNa₂SO₄, concentrated to give the crude, which was purified with prep-TLC(DCM/MeOH=10/1) to give theN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl-d2)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(20 mg, yield: 19%). ESI-MS [M+H]⁺: 448.2. Purity: 95.1%. ¹H NMR (400MHz, DMSO): δ 8.56 (s, 1H), 8.32-8.29 (m, 3H), 8.20 (s, 1H), 7.85 (s,1H), 7.78 (s, 1H), 7.71 (s, 1H), 7.39 (d, J=9.3 Hz, 1H), 6.99 (d, J=9.3Hz, 1H), 6.71-6.58 (m, 1H), 5.38 (s, 2H), 1.91 (ddd, J=13.3, 8.6, 5.1Hz, 1H), 0.91 (q, J=5.7 Hz, 2H), 0.66 (q, J=5.0 Hz, 2H).

Example 91

Synthesis of Methyl 2-(chloromethyl)imidazo[1,2-a]pyridine-6-carboxylate

The mixture of methyl 6-aminonicotinate (1.20 g, 7.88 mmol) and1,3-dichloropropan-2-one (2.0 g, 15.77 mmol) in DMF (10 mL) was heatedto 90° C. and stirred for 3 h. The reaction mixture was poured into H₂O(60 mL), adjusted pH to 9 by addition of aqueous NaHCO₃ and extractedwith EtOAc (60 mL×3). The combined organics were washed with brine (100mL), dried over anhydrous Na₂SO₄, concentrated and purified by columnchromatography (EtOAc/PE=1:1) to afford methyl2-(chloromethyl)imidazo[1,2-a]pyridine-6-carboxylate (570 mg, 32%) as ayellow solid. ESI-MS [M+H]⁺: 225.1.

Synthesis of Methyl2-((4-(((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-pyrazol-1-yl)methyl)imidazo[1,2-a]pyridine-6-carboxylate(I-91)

A mixture ofN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide(100 mg, 0.36 mmol), methyl2-(chloromethyl)imidazo[1,2-a]pyridine-6-carboxylate (90 mg, 0.40 mmol)and Cs₂CO₃ (235 mg, 0.72 mmol) in DMF (5 mL) was stirred for 2 h at 50°C. The reaction mixture was poured into H₂O (50 mL), solid wasprecipitated and filtered to give the crude product, which was purifiedby column chromatography (DCM:MeOH=10:1) to afford methyl2-((4-(((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-pyrazol-1-yl)methyl)imidazo[1,2-a]pyridine-6-carboxylate(70 mg, 42%) as a yellow solid. ESI-MS [M+H]⁺: 464.1. Purity: 99.39%. ¹HNMR (400 MHz, DMSO): δ 9.32 (s, 1H), 8.59 (t, J=5.5 Hz, 1H), 8.29 (m,3H), 8.01 (s, 1H), 7.88 (s, 1H), 7.79 (s, 1H), 7.60 (dd, J=25.5, 9.5 Hz,2H), 6.65 (dd, J=7.5, 1.8 Hz, 1H), 5.46 (s, 2H), 4.56 (d, J=5.6 Hz, 2H),3.87 (s, 3H).

Example 92

Synthesis of 2-amino-5-cyclopropylnicotinonitrile

To a mixture of 2-amino-5-bromonicotinonitrile (1 g, 5.1 mmol),cyclopropylboronic acid (647 mg, 7.6 mmol) and K₃PO₄ (3.78 g, 17.85mmol) in toluene/H₂O (20 mL/2 mL) was added Pd(OAc)₂ (114 mg, 0.51 mmol)and SPhos (209 mg, 0.51 mmol). The mixture was stirred at 95° C. for 16h. The reaction was cooled to RT and the reaction residue was filtered.The filtrate was concentrated to give the crude product which waspurified by silica gel chromatography (EA/PE=4/1) to give2-amino-5-cyclopropylnicotinonitrile (570 mg, yield: 71%) as a yellowsolid. ESI-MS [M+H]⁺: 160.1.

Synthesis of2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-carbonitrile

To a solution of 2-amino-5-cyclopropylnicotinonitrile (570 mg, 3.58mmol) in EtOH (20 mL) was added 1, 3-dichloropropan-2-one (1.37 g, 10.75mmol). The reaction mixture was stirred at 85° C. for 16 h. The reactionwas concentrated and the residue was diluted with NaHCO₃ (aq, 20 mL) andextracted with EtOAc (50 mL×3). The combined organic layers wereconcentrated to give the crude which was purified by silica gelchromatography (EA/PE=2/1) to give2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-carbonitrile (500mg, yield: 58%) as a yellow solid. ESI-MS [M+H]⁺: 232.1.

Synthesis ofN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((8-cyano-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(I-92)

To a mixture of2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-carbonitrile (80mg, 0.35 mmol) in dry DMF (5 mL) was addedN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide(95 mg, 0.35 mmol) and Cs₂CO₃ (338 mg, 1.04 mmol). The mixture wasstirred at RT for 16 h. Then H₂O (30 mL) was added to the reaction andextracted with EtOAc (30 mL×3). The combined organic layers were washedwith brine, dried over Na₂SO₄, filtered and concentrated to give thecrude, which was purified by prep-TLC (DCM/MeOH=10/1) to giveN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((8-cyano-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(34.5 mg, yield: 21%) as a white solid. ESI-MS [M+H]⁺: 471.1. Purity:98.67%. ¹H NMR (400 MHz, DMSO): δ 8.67 (d, J=1.5 Hz, 1H), 8.60 (t, J=5.7Hz, 1H), 8.31-8.29 (m, 2H), 8.24 (s, 1H), 7.87 (d, J=13.6 Hz, 2H), 7.78(t, J=1.9 Hz, 2H), 6.65 (dd, J=7.4, 2.1 Hz, 1H), 5.47 (s, 2H), 4.56 (d,J=5.7 Hz, 2H), 1.99-1.95 (m, 1H), 0.97-0.93 (m, 2H), 0.77-0.73 (m, 2H).

Example 93

Synthesis of Ethyl3-(4-(((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazol-3-yl)propanoate(I-93)

To a solution of3-(4-(((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazol-3-yl)propanoicacid (20 mg, 0.04 mmol) in EtOH (4 mL) was added SOCl₂ (0.5 mL). Thereaction was stirred at RT for 2 h. After concentration, the crudeproduct was purification by prep-TLC (DCM/MeOH=10/1) to give ethyl3-(4-(((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazol-3-yl)propanoate(13 mg, yield: 57%) as a white solid. ESI-MS [M+H]⁺: 546.2. Purity:89.6%. ¹H NMR (400 MHz, MeOD): δ 8.23 (s, 1H), 8.17-8.11 (m, 2H), 8.01(d, J=3.3 Hz, 1H), 7.71 (d, J=0.8 Hz, 1H), 7.66 (s, 1H), 7.35 (d, J=9.4Hz, 1H), 7.07 (dd, J=9.4, 1.7 Hz, 1H), 6.60 (dd, J=7.5, 2.0 Hz, 1H),5.33 (s, 2H), 4.65 (s, 2H), 4.03 (q, J=7.1 Hz, 2H), 3.15 (t, J=7.6 Hz,2H), 2.69 (t, J=7.6 Hz, 2H), 1.95-1.89 (m, 1H), 1.14 (t, J=7.1 Hz, 3H),1.01-0.90 (m, 2H), 0.72-0.66 (m, 2H).

Example 94

Synthesis ofN-(2-(7-chloroimidazo[1,5-a]pyridin-1-yl)ethyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (I-94)

A mixture of1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylicacid (60 mg, 0.2 mmol), 2-(7-chloroimidazo[1,5-a]pyridin-1-yl)ethanamine(60 mg, 0.2 mmol), HATU (90 mg, 0.24 mmol) and DIPEA (0.1 mL, 0.5 mmol)in DMF (10 mL) was stirred at RT for 16 h. H₂O (20 mL) was added toreaction and extracted with EtOAc (50 mL×3). The combined organic layerswere washed with brine, dried over Na₂SO₄ and concentrated in vacuo togive the crude, which was purified by prep-HPLC to giveN-(2-(7-chloroimidazo[1,5-a]pyridin-1-yl)ethyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(31 mg, yield: 33.8%) as a yellow solid. ESI-MS [M+H]⁺: 460.1. Purity:100.0%. H NMR (400 MHz, DMSO): δ 8.34 (s, 1H), 8.29 (s, 1H), 8.26 (d,J=7.4 Hz, 1H), 8.14 (s, 2H), 7.76 (d, J=22.4 Hz, 2H), 7.60 (d, J=0.9 Hz,1H), 7.40 (d, J=9.4 Hz, 1H), 7.00 (dd, J=9.4, 1.7 Hz, 1H), 6.57 (dd,J=7.5, 2.0 Hz, 1H), 5.39 (s, 2H), 3.44 (dd, J=13.2, 6.9 Hz, 3H), 2.95(t, J=7.2 Hz, 2H), 2.01-1.77 (m, 1H), 1.00-0.76 (m, 2H), 0.75-0.54 (m,2H).

Example 95

Synthesis of Ethyl1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-3-(difluoromethyl)-1H-pyrazole-4-carboxylate

A solution of 2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyrimidine (40mg, 0.19 mmol),N-((7-bromoimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide(60 mg, 0.19 mmol), and Cs₂CO₃ (248 mg, 0.76 mmol) in DMF (3 mL) wasstirred at RT for 2 h. Then the reaction mixture was diluted with H₂ (40mL) and extracted with EtOAc (30 mL×3). The combined organic layers weredried over Na₂SO₄ and concentrated to give the desired compound ethyl1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-3-(difluoromethyl)-1H-pyrazole-4-carboxylate(400 mg, yield: 67%) as brown oil, which was used in the next stepwithout purification. ESI-MS [M+H]⁺: 361.1.

Synthesis of1-((6-cyclopropylimidazo[1,2-a]pyridin-1-yl)methyl)-3-(difluoromethyl)-1H-pyrazole-4-carboxylic

A solution of ethyl1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-3-(difluoromethyl)-1H-pyrazole-4-carboxylate(400 mg, 1.11 mmol) and LiOH (233 mg, 5.55 mmol) in THF/EtOH/H₂O (10mL/10 mL/5 mL) was stirred at RT for 3 h. Most of the solvent wasconcentrated and the pH of the residue was adjusted to 4 by adding 1MHCl solution. Solid was precipitated and filtered to give1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-3-(difluoromethyl)-1H-pyrazole-4-carboxylicacid (300 mg, yield: 81%) as a brown solid, which was used in the nextstep without purification. ESI-MS [M+H]⁺: 333.1.

Synthesis ofN-((7-bromoimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-3-(difluoromethyl)-1H-pyrazole-4-carboxamide(I-95)

A solution of1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-3-(difluoromethyl)-1H-pyrazole-4-carboxylicacid (65 mg, 0.19 mmol), (7-bromoimidazo[1,5-a]pyridin-1-yl)methanaminehydrochloride (50 mg, 0.19 mmol), HATU (149 mg, 0.39 mmol) and DIPEA (76mg, 0.58 mmol) in DMF (5 mL) was stirred at RT for 2 h. Then thereaction mixture was diluted with H₂O (25 mL) and extracted with EtOAc(25 mL×3). The combined organic layers were washed with brine, driedover Na₂SO₄ and concentrated in vacuo to give the crude, which waspurified by column chromatography (PE/EA=10/1) to give the desiredcompoundN-((7-bromoimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-3-(difluoromethyl)-1H-pyrazole-4-carboxamide(18 mg, yield: 18%) as a white solid. ESI-MS [M+H]⁺: 540.1. Purity:98.48%. ¹H NMR (400 MHz, DMSO): δ 8.77 (s, 1H), 8.66 (s, 1H), 8.48 (s,1H), 8.39 (s, 1H), 8.26 (d, J=7.4 Hz, 1H), 8.14 (s, 1H), 7.97 (s, 1H),7.73 (d, J=9.3 Hz, 1H), 7.58 (d, J=8.7 Hz, 1H), 7.38 (t, J=53.8 Hz, 2H),6.83-6.76 (m, 1H), 5.69 (s, 2H), 4.59 (s, 2H), 2.11-2.02 (m, 1H),1.07-0.98 (m, 2H), 0.82-0.72 (m, 2H).

Example 96

Synthesis of2-((4-(((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-pyrazol-1-yl)methyl)imidazo[1,2-a]pyridine-6-carboxylicacid (I-96)

To a solution of methyl2-((4-(((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-pyrazol-1-yl)methyl)imidazo[1,2-a]pyridine-6-carboxylate(35 mg, 0.075 mmol) in methanol (2 mL), THF (2 mL) and H₂O (1 mL) wasadded lithium hydroxide monohydrate (44 mg, 1.05 mmol). The mixture wasstirred for 1 h at 40° C. The pH value of the residue was adjusted to 4by adding 1 M HCl solution. The resulting mixture was concentrated andpurified by prep-HPLC to give2-((4-(((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-pyrazol-1yl)methyl)imidazo[1,2-a]pyridine-6-carboxylicacid (25 mg, 74%) as a white solid. ESI-MS [M+H]⁺: 225.1. Purity:93.06%. ¹H NMR (400 MHz, DMSO): δ 13.15 (s, 1H), 9.25 (s, 1H), 8.59 (t,J=5.8 Hz, 1H), 8.31 (m, 2H), 8.25 (s, 1H), 7.98 (s, 1H), 7.87 (s, 1H),7.79 (s, 1H), 7.59 (m, 2H), 6.65 (dd, J=7.5, 2.0 Hz, 1H), 5.45 (s, 2H),4.56 (d, J=5.7 Hz, 2H).

Example 97

Synthesis ofN-((7-bromo-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(I-97)

To a solution of1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylicacid (60 mg, 0.21 mmol),(7-bromo-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride(84 mg, 0.32 mmol) and HATU (120 mg, 0.31 mmol) in DMF (5 mL) was addedDIPEA (81 mg, 0.63 mmol). The resulting reaction was stirred at RT for12 h. H₂O (25 mL) was added to the reaction, extracted with EtOAc (30mL×3). The combined organic layers were washed with brine, dried overNa₂SO₄ and concentrated in vacuo to give the crude, which was purifiedwith prep-TLC (DCM/MeOH=10/1) to theN-((7-bromo-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(20 mg, yield: 19%) as a white solid. ESI-MS [M+H]⁺: 508.1. Purity:98.9%. ¹H NMR (400 MHz, DMSO): δ 8.46 (d, J=2.2 Hz, 1H), 8.42 (t, J=4.8Hz, 1H), 8.33 (s, 1H), 8.20 (s, 1H), 8.14 (d, J=7.3 Hz, 1H), 7.84 (s,1H), 7.72 (s, 1H), 7.39 (d, J=9.3 Hz, 1H), 6.99 (d, J=9.3 Hz, 1H), 6.82(t, J=6.6 Hz, 1H), 5.39 (s, 2H), 4.62 (d, J=5.2 Hz, 2H), 1.94-1.88 (m,1H), 0.95-0.87 (m, 2H), 0.71-0.61 (m, 2H).

Example 98

Synthesis of1-((6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methyl)-N-((7-ethynylimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide(I-98)

A solution of1-((6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methyl)-1H-pyrazole-4-carboxylicacid (66 mg, 0.23 mmol),(7-ethynylimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride (47 mg,0.23 mmol), HATU (175 mg, 0.46 mmol) and DIPEA (89 mg, 0.69 mmol) in DMF(5 mL) was stirred at RT for 2 h. Then the reaction mixture was dilutedwith H₂O (30 mL) and extracted with EtOAc (30 mL×3). The combinedorganic layers were washed with brine, dried over Na₂SO₄ andconcentrated to give the crude, which was purified by prep-HPLC to give1-((6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methyl)-N-((7-ethynylimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide(10 mg, yield: 10%) as a white solid. ESI-MS [M+H]⁺: 437.2. Purity:97.51%. ¹H NMR (400 MHz, DMSO): δ 8.61 (t, J=5.6 Hz, 1H), 8.48 (s, 1H),8.27 (d, J=7.1 Hz, 1H), 8.22 (s, 1H), 8.10 (s, 1H), 7.96-7.91 (m, 2H),7.85 (s, 1H), 7.11 (t, J=7.7 Hz, 1H), 6.63 (d, J=7.3 Hz, 1H), 5.42 (s,2H), 4.60 (d, J=5.7 Hz, 2H), 4.30 (s, 1H), 2.22-2.13 (m, 1H), 1.10-1.03(m, 2H), 1.00-0.94 (m, 2H).

Example 99

Synthesis of Ethyl1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-3-(difluoromethyl)-1H-pyrazole-4-carboxylate

A mixture of 2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyrimidine (40mg, 0.19 mmol),N-((7-bromoimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide(60 mg, 0.19 mmol) and Cs₂CO₃ (248 mg, 0.76 mmol) in DMF (2 mL) wasstirred at RT for 2 h. Then the reaction mixture was diluted with H₂O(40 mL) and extracted with EtOAc (30 mL×3). The combined organic layerswere washed with brine, dried over Na₂SO₄ and concentrated to give thedesired compound ethyl1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-3-(difluoromethyl)-1H-pyrazole-4-carboxylate(400 mg, yield: 67%) as brown oil, which was used in the next stepwithout purification. ESI-MS [M+H]⁺: 361.1.

Synthesis of1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-3-(difluoromethyl)-1H-pyrazole-4-carboxylic

A solution of ethyl1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-3-(difluoromethyl)-1H-pyrazole-4-carboxylate(400 mg, 1.11 mmol) and LiOH (233 mg, 5.55 mmol) in THF/EtOH/H₂O (10mL/10 mL/5 mL) was stirred at RT for 3 h. Most of the solvent wasconcentrated and the pH of the residue was adjusted to 4 by adding 1 MHCl solution. Solid was precipitated and filtered to give the desiredcompound1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-3-(difluoromethyl)-1H-pyrazole-4-carboxylicacid (300 mg, yield: 81%) as a brown solid, which was used in the nextstep without purification. ESI-MS [M+H]⁺: 333.2.

Synthesis ofN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-3-(difluoromethyl)-1H-pyrazole-4-carboxamide(I-99)

A solution of1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-3-(difluoromethyl)-1H-pyrazole-4-carboxylicacid (65 mg, 0.19 mmol), (7-chloroimidazo[1,5-a]pyridin-1-yl)methanaminehydrochloride (41 mg, 0.19 mmol), HATU (149 mg, 0.39 mmol) and DIPEA (76mg, 0.58 mmol) in DMF (5 mL) was stirred at RT for 2 h. Then thereaction mixture was diluted with H₂O (30 mL) and extracted with EtOAc(30 mL×3). The combined organic layers were washed with brine, driedover Na₂SO₄ and concentrated to give the crude, which was purified bycolumn chromatography (DCM/MeOH=10/1) to give the desired compoundN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-3-(difluoromethyl)-1H-pyrazole-4-carboxamide(18 mg, yield: 18%) as a white solid. ESI-MS [M+H]⁺: 496.2. Purity:91.43%. ¹H NMR (400 MHz, DMSO): δ 8.61 (t, J=5.6 Hz, 1H), 8.48 (s, 1H),8.27 (d, J=7.1 Hz, 1H), 8.22 (s, 1H), 8.10 (s, 1H), 7.96-7.91 (m, 2H),7.85 (s, 1H), 7.11 (t, J=7.7 Hz, 1H), 6.63 (d, J=7.3 Hz, 1H), 5.42 (s,2H), 4.60 (d, J=5.7 Hz, 2H), 4.30 (s, 1H), 2.22-2.13 (m, 1H), 1.10-1.03(m, 2H), 1.00-0.94 (m, 2H).

Example 100

Synthesis ofN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(hydroxymethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide

To a mixture of(2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)methanol (370mg, 1.56 mmol) in dry DMF (10 mL) was addedN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide(430 mg, 1.56 mmol) and Cs₂CO₃ (1.53 g, 4.68 mmol). The mixture wasstirred at 25° C. for 16 h. Then H₂O (50 mL) was added and extractedwith EtOAc (50 mL×3). The combined organic layers were washed withbrine, dried over Na₂SO₄, filtered and concentrated to give the crude,which was purified by silica gel chromatography (DCM/MeOH=10/1) to giveN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(hydroxymethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(400 mg, yield: 53.8%) as a yellow solid. ESI-MS [M+H]⁺: 476.2.

Synthesis ofN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-formylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide

To a mixture ofN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(hydroxymethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(400 mg, 0.84 mmol) in DMSO (10 mL) was added 2-iodoxybenzoic acid (472mg, 1.68 mmol). The mixture was stirred at 40° C. for 4 h. Then H₂O (80mL) was added, and the precipitate was filtered and dried to giveN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-formylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(200 mg, yield: 50%) as a white solid, which was used in the next stepwithout purification. ESI-MS [M+H]⁺: 474.1.

Synthesis of Ethyl3-(2-((4-(((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-pyrazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)acrylate(I-100a)

To a mixture ofN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-formylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(200 mg, 0.4 mmol) in dry THF (8 mL) was added Ethyl(triphenylphosphoranylidene)acetate (152 mg, 0.44 mmol) at 0° C. Themixture was stirred at 25° C. for 6 h, concentrated to give the crude,which was purified by Pre-TLC (DCM/MeOH=10/1) to give ethyl3-(2-((4-(((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-pyrazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)acrylate(120 mg, yield: 52%) as a yellow solid. ESI-MS [M+H]⁺: 544.2. purity:93.12%.

¹H NMR (400 MHz, DMSO) δ 8.59 (t, J=5.7 Hz, 1H), 8.43-8.42 (m, 1H),8.31-8.29 (m, 2H), 8.22 (s, 1H), 7.90 (s, 1H), 7.79-7.75 (m, 3H),7.64-7.60 (m, 1H), 7.44-7.43 (m, 1H), 6.64 (dd, J=7.4, 2.1 Hz, 1H), 5.47(s, 2H), 4.55 (d, J=5.7 Hz, 2H), 4.20 (q, J=7.1 Hz, 2H), 1.95-1.91 (m,1H), 1.27 (t, J=7.1 Hz, 3H), 0.94-0.91 (m, 2H), 0.76-0.72 (m, 2H).

Synthesis of Ethyl3-(2-((4-(((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-pyrazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)propanoate(I-100b)

To a mixture of ethyl3-(2-((4-(((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-pyrazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)acrylate(120 mg, 0.22 mmol) in MeOH (5 mL) was CuCl (43 mg, 0.44 mmol) and NaBH₄(25 mg, 0.66 mmol). The mixture was stirred at 25° C. for 16 h. Water(30 mL) was added and extracted with EtOAc (50 mL×3). The combinedorganic layers were washed with brine, dried over Na₂SO₄, filtered andconcentrated to give the crude, which was purified by prep-TLC(DCM/MeOH=10/1) to give ethyl3-(2-((4-(((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-pyrazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)propanoate(110 mg, yield: 91%) as a yellow solid. ESI-MS [M+H]⁺: 546.2. Purity:99.11%. H NMR (400 MHz, DMSO): δ 8.59 (t, J=5.5 Hz, 1H), 8.31-8.29 (m,2H), 8.20-8.19 (m, 2H), 7.88 (s, 1H), 7.78 (s, 1H), 7.66 (s, 1H), 6.82(s, 1H), 6.64 (dd, J=7.4, 2.0 Hz, 1H), 5.40 (s, 2H), 4.55 (d, J=5.6 Hz,2H), 4.04 (q, J=7.1 Hz, 2H), 3.07 (t, J=7.6 Hz, 2H), 2.77 (t, J=7.6 Hz,2H), 1.90-1.84 (m, 1H), 1.14 (t, J=7.1 Hz, 3H), 0.92-0.87 (m, 2H),0.66-0.62 (m, 2H).

Synthesis of3-(2-((4-(((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-pyrazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)propanoicacid (I-100c)

To a mixture of ethyl3-(2-((4-(((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-pyrazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)propanoate(40 mg, 0.07 mmol) in THF/EtOH/H₂O (1 mL/1 mL/1 mL) was added LiOH (5.3mg, 0.22 mmol). The mixture was stirred at 25° C. for 6 h. The pH of theresidue was adjusted to 4 by adding 1 M HCl solution. The mixture wasconcentrated and purified by prep-HPLC to give3-(2-((4-(((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-pyrazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)propanoicacid (14 mg, yield: 37%) as a yellow solid. ESI-MS [M+H]⁺: 518.2.Purity: 99.18%. ¹H NMR (400 MHz, DMSO) δ 12.18 (s, 1H), 8.59 (t, J=5.6Hz, 1H), 8.31-8.29 (m, 2H), 8.20-8.18 (m, 2H), 7.88 (s, 1H), 7.78 (s,1H), 7.65 (s, 1H), 6.82 (s, 1H), 6.66-6.63 (m, 1H), 5.40 (s, 2H), 4.55(d, J=5.6 Hz, 2H), 3.04 (t, J=7.5 Hz, 2H), 2.69 (t, J=7.6 Hz, 2H),1.89-1.85 (m, 1H), 0.90-0.88 (m, 2H), 0.66-0.64 (m, 2H).

Example 101

Synthesis ofN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(hydroxymethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide

To a mixture of(2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)methanol (370mg, 1.56 mmol) in dry DMF (10 mL) was addedN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide(430 mg, 1.56 mmol) and Cs₂CO₃ (1.53 g, 4.68 mmol). The mixture wasstirred at 25° C. for 16 h. Then H₂O (100 mL) was added to the reactionand extracted with EtOAc (100 mL×3). The combined organic layers werewashed with brine, dried over Na₂SO₄, filtered and concentrated to givethe crude, which was purified by prep-TLC (DCM/MeOH=10/1) to giveN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(hydroxymethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(400 mg, yield: 53.9%) as a yellow solid. ESI-MS [M+H]⁺: 476.1.

Synthesis ofN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((8-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide

To a mixture ofN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(hydroxymethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(50 mg, 0.1 mmol) in THF (2 mL) was added SOCl₂ (0.5 mL). The mixturewas stirred at 25° C. for 3 h. Then the reaction mixture wasconcentrated to giveN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((8-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(50 mg, yield: 96%) as a yellow solid, which was used into the next stepwithout purification. ESI-MS [M+H]⁺: 494.1.

Synthesis ofN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(morpholinomethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (I-101)

To a mixture ofN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((8-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(50 mg, 0.1 mmol) in dry DMF (3 mL) was added morpholine (17.6 mg, 0.2mmol) and Cs₂CO₃ (163 mg, 0.5 mmol). The mixture was stirred at 25° C.for 16 h. Water (30 mL) was added and extracted with EtOAc (50 mL×3).The combined organic layers were washed with brine, dried over Na₂SO₄,filtered and concentrated to give the crude, which was purified byprep-TLC (DCM/MeOH=8/1) to giveN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(morpholinomethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(11.6 mg, yield: 21%) as a white solid. ESI-MS [M+H]⁺: 545.2. Purity:99.15%. ¹H NMR (400 MHz, DMSO): δ 8.58 (t, J=5.7 Hz, 1H), 8.31-8.29 (m,2H), 8.22-8.19 (m, 2H), 7.87 (s, 1H), 7.77 (m, 1H), 7.68 (s, 1H), 6.99(s, 1H), 6.64 (dd, J=7.5, 2.1 Hz, 1H), 5.39 (s, 2H), 4.55 (d, J=5.7 Hz,2H), 3.75 (s, 2H), 3.60-3.58 (m, 4H), 2.44 (s, 4H), 1.96-1.89 (m, 1H),0.94-0.89 (m, 2H), 0.66-0.62 (m, 2H).

Example 102

Synthesis of Ethyl3-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carboxylate

To a solution of ethyl 3-bromo-1H-pyrazole-4-carboxylate (547 mg, 2.5mmol) and NaH (150 mg, 3.75 mmol, 60% oil) in THF (5 mL) and under N₂was added SEMCl (458 mg, 2.75 mmol) at 0° C. The reaction mixture wasstirred at RT for 2 h. The reaction was quenched with H₂O (30 mL) andextracted with EtOAc (30 mL×2). The combined organic layers were washedwith brine, dried over Na₂SO₄ and concentrated in vacuo to afford ethyl3-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carboxylateas a yellow oil (873 mg, yield: 99%) and a mixture of N1 and N2regioisomers. ESI-MS [M+H]⁺: 350.1.

Synthesis of Ethyl3-(3-hydroxyoxetan-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carboxylate

To a solution of ethyl3-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carboxylate(615 mg, 1.76 mmol) in THF (8 mL) under N₂ was added BuLi (0.9 mL, 2.11mmol, 2.4 M solution in hexane) at −78° C. Then oxetan-3-one (2.1 mL,35.2 mmol) was added. The reaction was allowed to warm to RT and stirredfor 2 h. The reaction mixture was quenched with saturated NH₄Cl solution(20 mL) and extracted with EtOAc (50 mL×3). The combined organic layerswere washed with brine, dried over Na₂SO₄ and concentrated in vacuo togive crude, which was purified by a column flash (PE:EA=2:1) to getethyl3-(3-hydroxyoxetan-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carboxylate(169 mg, yield: 28%) as a yellow oil. ESI-MS [M+H]⁺: 343.2.

Synthesis of Ethyl3-(3-(((methylthio)carbonothioyl)oxy)oxetan-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carboxylate

To a mixture of NaH (54 mg, 1.34 mmol, 60% oil) in THF (1 mL) was addeda solution of ethyl3-(3-hydroxyoxetan-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carboxylate(306 mg, 0.89 mmol) in THF (0.5 mL) at 0° C. dropwise. The resultingsolution was stirred at 0° C. for 30 min. Then a solution of CS₂ (102mg, 1.34 mmol) in THF (0.5 mL) was added to the reaction at 0° C.dropwise. The resulting solution was stirred at 0° C. for another 1 h.To the mixture above was added a solution of iodomethane (190 mg, 1.34mmol) in THF (0.5 mL) dropwise at 0° C. The resulting solution wasstirred at 0° C. for 1 h, then quenched with aqueous NH₄Cl (10 mL), andextracted with EtOAc (50 mL×3). The combined organic layers were washedwith brine, dried over Na₂SO₄ and concentrated in vacuo to afford ethyl3-(3-(((methylthio)carbonothioyl)oxy)oxetan-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carboxylate(385 mg crude) as yellow oil, which was used into next step withoutfurther purification. ESI-MS [M+H]⁺: 433.1.

Synthesis of Ethyl3-(oxetan-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carboxylate

To a solution of ethyl3-(3-(((methylthio)carbonothioyl)oxy)oxetan-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carboxylate(385 crude from previous step) in toluene (10 mL) were added Bu₃SnH (311mg, 1.07 mmol) and AIBN (29 mg, 0.18 mmol). The resulting mixture wasstirred at 120° C. for 3 h. The reaction was cooled to RT andconcentrate in vacuo to give the crude, which was purified by silica gelcolumn (PE/EA=5/1) to isolate ethyl3-(oxetan-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carboxylate(204 mg, yield: 70%) as yellow oil. ESI-MS [M+H]⁺: 327.2.

Synthesis of Ethyl 3-(oxetan-3-yl)-1H-pyrazole-4-carboxylate

To a solution of TBAF (3.2 mL, 3.13 mmol, 1 M solution in THF) was addedethyl3-(oxetan-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carboxylate(204 mg, 0.63 mmol). The mixture was stirred at 90° C. for 8 h. H₂O (25mL) was added to the reaction and extracted with EtOAc (35 mL×3). Thecombined organic layer were washed with brine, dried over Na₂SO₄ andconcentrated in vacuo. The residue was purified by silica gel column(PE/EA=1/2) to isolate ethyl 3-(oxetan-3-yl)-1H-pyrazole-4-carboxylate(81 mg, yield: 66%) as a white solid. ESI-MS [M+H]⁺: 197.2.

Synthesis of Ethyl1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-3-(oxetan-3-yl)-1H-pyrazole-4-carboxylate

To a solution of ethyl 3-(oxetan-3-yl)-1H-pyrazole-4-carboxylate (50 mg,0.25 mmol) in DMF (5 mL) was added2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine (63 mg, 0.31 mmol)and Cs₂CO₃ (245 mg, 0.75 mmol). The mixture was stirred at RT for 3 h.Water (20 mL) was added and extracted with EtOAc (30 mL×2). The combinedorganic layers were washed with brine, dried over Na₂SO₄ andconcentrated in vacuo to give a residue, which was purified by silicagel column (DCM/MeOH=20/1) to give ethyl 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-3-(oxetan-3-yl)-1H-pyrazole-4-carboxylate(90 mg, yield: 98%) as a white solid. ESI-MS [M+H]⁺: 367.2.

Synthesis of1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-3-(oxetan-3-yl)-1H-pyrazole-4-carboxylicAcid

To a solution of ethyl1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-3-(oxetan-3-yl)-1H-pyrazole-4-carboxylate(45 mg, 0.12 mmol) in THF/EtOH/H₂O (2 mL/2 mL/1 mL) was added LiOH (10mg, 0.24 mmol). The resulting mixture was stirred at 50° C. for 3 h. Themixture was freeze-dried to give1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-3-(oxetan-3-yl)-1H-pyrazole-4-carboxylicacid as a lithium salt (50 mg crude), which was used in the next stepwithout purification. ESI-MS [M+H]⁺: 339.2.

Synthesis ofN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-3-(oxetan-3-yl)-1H-pyrazole-4-carboxamide(I-102)

To a solution of ethyl1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-3-(oxetan-3-yl)-1H-pyrazole-4-carboxylicacid (50 mg crude from previous step) in DMF (3 mL) was added(7-chloroimidazo[1,5-a]pyridin-1-yl)methanamine (22 mg, 0.12 mmol), HATU(91 mg, 0.24 mmol) and DIPEA (47 mg, 0.36 mmol). The mixture was stirredat RT for 14 h. H₂O (20 mL) was added to the reaction and extracted withEtOAc (30 mL×3). The combined organic layers were washed with brine,dried over Na₂SO₄ and concentrated in vacuo to give a residue. Theresidue was purified by flash silica gel column (DCM/MeOH=8/1) toisolateN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-3-(oxetan-3-yl)-1H-pyrazole-4-carboxamide(34.8 mg, yield: 58%) as a white solid. ESI-MS [M+H]⁺: 502.1. Purity:97.10%. ¹H NMR (400 MHz, DMSO): δ 8.43 (t, J=5.8 Hz, 1H), 8.34 (s, 1H),8.30-8.29 (m, 2H), 8.21 (s, 1H), 7.77 (s, 1H), 7.74 (d, J=1.9 Hz, 1H),7.39 (d, J=9.3 Hz, 1H), 7.00 (dd, J=9.4, 1.7 Hz, 1H), 6.64 (dd, J=7.5,2.1 Hz, 1H), 5.36 (s, 2H), 4.83-4.82 (m, J=8.4, 2H), 4.71-4.68 (m, 2H),4.60-4.54 (m, 1H), 4.50 (d, J=5.7 Hz, 2H), 1.95-1.88 (m, 1H), 0.94-0.89(m, 2H), 0.68-0.64 (m, 2H).

Example 103

Synthesis of Ethyl1-((8-((2-methoxyethoxy)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate

To a mixture of ethyl1-((8-(hydroxymethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate(200 mg, 0.59 mmol) in THF (10 mL) was added 2-methoxyethyl4-methylbenzenesulfonate (1.4 g, 5.9 mmol) and NaH (25 mg, 0.88 mmol).The resulting mixture was stirred at 60° C. for 12 h. Then reaction wasquenched with H₂O (10 mL) and extracted with EtOAc (30 mL×3). Thecombined organic layers were washed with brine, dried over Na₂SO₄ andconcentrated in vacuo to give the crude. The crude was purified withprep-TLC (PE/EA=3/1) to give the ethyl1-((8-((2-methoxyethoxy)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate(158 mg, yield: 70%) as a white solid. ESI-MS [M+H]⁺: 385.1.

Synthesis of1-((6-cyclopropyl-8-(2-methoxyethoxy)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylicAcid

To a mixture of ethyl1-((6-cyclopropyl-8-(2-methoxyethoxy)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate(158 mg, 0.41 mmol) in EtOH (5 mL) was added NaOH (64 mg, 1.6 mmol) inH₂O (2 mL). The mixture was stirred at 50° C. for 3 h. The pH value ofthe reaction was adjusted to 2-3. The resulting mixture was concentratedto give1-((6-cyclopropyl-8-(2-methoxyethoxy)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylicacid (210 mg, crude) as a white solid which was used in the next stepwithout purification. ESI-MS [M+H]⁺: 357.1.

Synthesis ofN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(2-methoxyethoxy)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(I-103)

To a mixture of1-((6-cyclopropyl-8-(2-methoxyethoxy)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylicacid (210 mg, crude from last step) in DMF (5 mL) was added(7-chloroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride (126 mg,0.58 mmol), DIPEA (146 mg, 1.45 mmol) and HATU (1.67 g, 0.44 mmol). Themixture was stirred at RT for 3 h. The reaction was quenched with H₂O(30 mL) and was extracted with EtOAc (30 mL×3). The combined organiclayers were washed with brine, dried over Na₂SO₄ and concentrated invacuo to give the crude, which was purified with prep-TLC(DCM/MeOH=10/1) to give theN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(2-methoxyethoxy)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(28.7 mg, yield: 13% in 2 steps) as a white solid. ESI-MS [M+H]⁺: 534.2.Purity: 98.1%. ¹H NMR (400 MHz, DMSO): δ 8.69 (t, J=5.6 Hz, 1H), 8.62(s, 1H), 8.57 (s, 1H), 8.36 (d, J=7.5 Hz, 1H), 8.32 (s, 1H), 8.11 (s,1H), 7.97 (s, 1H), 7.87 (s, 1H), 7.64 (s, 1H), 6.77 (d, J=7.3 Hz, 1H),5.63 (s, 2H), 4.78 (s, 2H), 4.61 (d, J=5.6 Hz, 2H), 3.63-3.56 (m, 2H),3.53-3.37 (m, 2H), 3.20 (s, 3H), 2.10-2.04 (m, 1H), 1.06-1.02 (m, 2H),0.79-0.75 (m, 2H).

Example 104

Synthesis of1-((8-acetyl-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide(I-104a)

A mixture of ethyl2-((4-(((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-pyrazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-carboxylate(150 mg, 0.29 mmol) in THF (5 mL) was added CH₃MgBr (1 M in THF, 1.45mL, 1.45 mmol) at 0° C. The mixture was stirred at 0° C. for 3 h underN₂. The reaction was quenched with saturated NH₄Cl (aq., 3 mL) andextracted with EtOAc (30 mL×3). The combined organic layers were washedwith brine, dried over Na₂SO₄ and concentrated in vacuo to give thecrude, which was purified with prep-HPLC to give1-((8-acetyl-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide(1.5 mg, yield: 1.05%) as a white solid. ESI-MS [M+H]⁺: 488.2. Purity:95.1%. ¹H NMR (400 MHz, MeOD): δ 8.85 (s, 1H), 8.72 (d, J=1.0 Hz, 1H),8.45 (d, J=1.4 Hz, 1H), 8.34-8.30 (m, 2H), 8.06 (s, 1H), 7.98 (s, 1H),7.92 (s, 1H), 6.89 (dd, J=7.5, 1.8 Hz, 1H), 5.71 (s, 2H), 4.77 (s, 2H),2.78 (s, 3H), 2.22-2.17 (m, 1H), 1.20-1.12 (m, 2H), 1.01-0.87 (m, 2H).

From the above reaction,N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(2-hydroxypropan-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(I-104b) was also isolated (3.8 mg, yield: 2.6%) as a white solid.ESI-MS [M+H]⁺: 504.2. Purity: 98.1%. ¹H NMR (400 MHz, MeOD): δ 8.15 (s,1H), 8.06-8.05 (m, 2H), 7.98 (s, 1H), 7.82 (s, 1H), 7.63 (s, 1H), 7.55(s, 1H), 7.06 (s, 1H), 6.55-6.49 (m, 1H), 5.38 (s, 2H), 4.58 (s, 2H),1.87-1.79 (m, 1H), 1.58 (s, 6H), 0.91-0.83 (m, 2H), 0.65-0.58 (m, 2H).

Example 105

Synthesis of Ethyl2-(2-((4-(((7-bromo-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-pyrazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)acetate(I-105)

To a mixture of1-((6-cyclopropyl-8-(2-ethoxy-2-oxoethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylicacid (150 mg, 0.42 mmol) in DMF (5 mL) was added(7-bromo-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride(235 mg, 0.84 mmol), DIPEA (150 mg, 1.15 mmol) and HATU (240 mg, 0.63mmol). The mixture was stirred at RT for 3 h. H₂O (30 mL) was added andthe reaction was extracted with EtOAc (50 mL×3). The combined organiclayers were washed with brine, dried over Na₂SO₄ and concentrated invacuo to give the crude, which was purified with prep-HPLC to give the2-(2-((4-(((7-bromo-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-pyrazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)acetate(21.6 mg, yield: 10.2%) as a white solid. ESI-MS [M+H]⁺: 494.1. Purity:97.7%. ¹H NMR (400 MHz, DMSO): δ 8.61 (s, 1H), 8.49-8.47 (m, 2H), 8.30(s, 1H), 8.15 (d, J=7.4 Hz, 1H), 8.08 (s, 1H), 7.96 (s, 1H), 7.56 (s,1H), 6.84 (dd, J=7.2, 6.2 Hz, 1H), 5.62 (s, 2H), 4.64 (d, J=5.2 Hz, 2H),4.11-4.06 (m, 4H), 2.07-2.00 (m, 1H), 1.16 (t, J=7.1 Hz, 3H), 1.06-1.01(m, 2H), 0.77-0.73 (m, 2H).

Example 106

Synthesis of2-(2-((4-(((7-bromo-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-pyrazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)aceticacid (I-106)

To a solution of ethyl2-(2-((4-(((7-bromo-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-pyrazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)acetate(20 mg, 0.034 mmol) in EtOH (2 mL) was added NaOH (4 mg, 0.16 mmol) inH₂O (1 mL). The mixture was stirred at RT for 3 h. The pH of the mixturewas adjusted to 2-3. The resulting mixture was concentrated to give thecrude, which was purified by prep-HPLC to give2-(2-((4-(((7-bromo-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-pyrazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)aceticacid (7.1 mg, yield: 37%) as a white solid. ESI-MS [M+H]⁺: 566.1.Purity: 92.9%. ¹H NMR (400 MHz, DMSO): δ 8.48-8.38 (m, 2H), 8.36 (s,1H), 8.20-8.18 (m, 2H), 8.14 (d, J=7.3 Hz, 1H), 7.86 (s, 1H), 7.65 (s,1H), 6.91 (s, 1H), 6.82 (t, J=6.6 Hz, 1H), 5.38 (s, 2H), 4.62 (d, J=4.9Hz, 2H), 3.72 (s, 2H), 1.90-1.86 (m, 1H), 0.93-0.85 (m, 2H), 0.66-0.61(m, 2H).

Example 107

Synthesis ofN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(3-hydroxypropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(I-107)

To a solution of ethyl 3-(2-((4-((7-chloroimidazo[1,5-a]pyridin-1-yl)methylcarbamoyl)-1H-pyrazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)propanoate(35 mg, 0.064 mmol) in THF/MeOH (5 mL/0.5 mL) was added LiBH₄ (7 mg,0.321 mmol) at 0° C. The resulting reaction was stirred at RT for 4 h.H₂O (15 mL) was added to the reaction and extracted with EtOAc (30mL×3). The combined organic layers were washed with brine, dried overNa₂SO₄ and concentrated in vacuo to give the crude, which was purifiedwith prep-TLC (DCM/MeOH=10/1) to giveN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(3-hydroxypropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(10 mg, yield: 31%) as a white solid. ESI-MS [M+H]⁺: 504.2. Purity:97.9%. ¹H NMR (400 MHz, DMSO): δ 8.58 (t, J=5.7 Hz, 1H), 8.32-8.28 (m,2H), 8.22-8.15 (m, 2H), 7.88 (s, 1H), 7.78 (s, 1H), 7.64 (s, 1H), 6.80(s, 1H), 6.66-6.62 (m, 1H), 5.39 (s, 2H), 4.57-4.52 (m, 3H), 3.44-3.92(m, 2H), 2.88-2.78 (m, 2H), 1.94-1.77 (m, 3H), 0.92-0.87 (m, 2H),0.69-0.59 (m, 2H).

Example 108

Synthesis ofN-((7-bromo-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methyl)-1H-pyrazole-4-carboxamide(I-108)

A mixture of1-((6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methyl)-1H-pyrazole-4-carboxylicacid (46 mg, 0.16 mmol), HATU (76 mg, 0.20 mmol) and DIPEA (103 mg, 0.80mmol) in dry DMF (4 mL) was stirred at RT for 1 h. Then(7-bromo-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine (40 mg, 0.16mmol) was added. The resulting mixture was stirred at RT for another 1h. Water (30 mL) was added and the mixture was extracted with ethylacetate (30 mL×3). The combined organic layers were washed with brine,dried over anhydrous Na₂SO₄ and concentrated to give a residue, whichwas purified by prep-HPLC to giveN-((7-bromo-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methyl)-1H-pyrazole-4-carboxamide(8 mg, yield: 9.7%) as a white solid. ESI-MS [M+H]⁺: 509.1. Purity:98.27%. ¹H NMR (400 MHz, DMSO): δ 8.46 (d, J=2.4 Hz, 1H), 8.40 (t, J=5.2Hz, 1H), 8.20 (s, 1H), 8.14 (d, J=7.4 Hz, 1H), 8.10 (s, 1H), 7.93 (d,J=9.5 Hz, 1H), 7.83 (s, 1H), 7.11 (d, J=9.5 Hz, 1H), 6.85-6.79 (m, 1H),5.42 (s, 2H), 4.62 (d, J=5.2 Hz, 2H), 2.22-2.13 (m, 1H), 1.12-1.03 (m,2H), 1.00-0.94 (m, 2H).

Example 109

Synthesis of Ethyl2-(2-((4-(((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-pyrazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)acetate

To a mixture of1-((6-cyclopropyl-8-(2-ethoxy-2-oxoethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylicacid (150 mg, 0.41 mmol) in DMF (3 mL) was added(7-chloroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride (107 mg,0.49 mmol), DIPEA (0.49 mL, 3 mmol) and HATU (234 mg, 0.62 mmol). Themixture was stirred at RT for 3 h. The reaction was diluted with H₂O (30mL) and extracted with EtOAc (30 mL×3). The combined organic layers werewashed with brine, dried over Na₂SO₄, and concentrated in vacuo to givethe crude which was purified by prep-TLC (DCM/MeOH=10/1) to give ethyl2-(2-((4-(((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-pyrazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)acetate(70 mg, yield: 32%) as a white solid. ESI-MS [M+H]⁺: 532.1.

Synthesis ofN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(2-hydroxy-2-methylpropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(I-109)

To a mixture of ethyl2-(2-((4-(((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-pyrazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)acetate(70 mg, 0.13 mmol) in THF (5 mL) was added CH₃MgBr (1 M in THF, 0.65 mL,0.65 mmol) at 0° C. The mixture was stirred at 0° C. for 3 h under N₂.The reaction was quenched with NH₄Cl (10 mL) and extracted with EtOAc(30 mL×3). The combined organic layers were washed with brine, driedover Na₂SO₄ and concentrated in vacuo to give the crude, which waspurified by prep-HPLC to giveN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(2-hydroxy-2-methylpropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(5.4 mg, yield: 8%) as a white solid. ESI-MS [M+H]⁺: 518.2. Purity:99.1%. 1H NMR (400 MHz, DMSO): δ 8.58 (s, 1H), 8.32-8.30 (m, 2H), 8.18(d, J=8.3 Hz, 2H), 7.88 (s, 1H), 7.78 (s, 1H), 7.65 (s, 1H), 6.90 (s,1H), 6.65 (d, J=7.3 Hz, 1H), 5.39 (s, 2H), 5.24 (s, 1H), 4.56 (d, J=5.2Hz, 2H), 2.98 (s, 2H), 1.92-1.85 (m, 1H), 1.06 (s, 6H), 0.94-0.88 (m,2H), 0.67-0.62 (m, 2H).

Example 110

Synthesis of 2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine

A mixture of 5-cyclopropylpyridin-2-amine (320 mg, 2.38 mmol),1,3-dichloropropan-2-one (906 mg, 7.14 mmol) in EtOH (5 mL) was stirredat 90° C. for 18 h. Saturated aqueous NaHCO₃ (20 mL) was added and themixture was extracted with EtOAc (50 mL×2). The combined organic layerswere washed with brine, dried over Na₂SO₄ and concentrated to give thecrude product which was purified by silica gel chromatography(EA/PE=2/1) to give 2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine(200 mg, yield: 41%) as a brown solid. ESI-MS [M+H]⁺: 207.1.

Synthesis of2-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-2H-tetrazole-5-carboxylicAcid

A mixture of 2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine (104mg, 0.5 mmol), ethyl 1H-tetrazole-5-carboxylate (71 mg, 0.5 mmol) andCs₂CO₃ (978 mg, 3 mmol) in DMF (5 mL) was stirred at 55° C. for 6 h.After cooled to RT, H₂O (30 mL) was added and the mixture was extractedwith EtOAc (30 mL×3). The pH value of the H₂O layer was adjusted to 5-6by adding 1 M aqueous HCl solution, then freeze-dried to give2-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-2H-tetrazole-5-carboxylicacid (71 mg, yield: 50%) as a yellow solid. This was used into next stepwithout purification. ESI-MS [M+H]⁺: 285.1.

Synthesis ofN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-2-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-2H-tetrazole-5-carboxamide(I-109)

A mixture of2-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-2H-tetrazole-5-carboxylicacid (71 mg, 0.25 mmol), (7-chloroimidazo[1,5-a]pyridin-1-yl)methanamine(36 mg, 0.2 mmol), HATU (190 mg, 0.5 mmol) and DIPEA (97 mg, 0.75 mmol)in DMF (3 mL) was stirred at RT for 2 h. Water (20 mL) was added andextracted with EtOAc (30 mL×3). The combined organic layers were washedwith brine, dried over Na₂SO₄ and concentrated to give the crudeproduct, which was purified by silica gel column chromatography(CH₂Cl₂/CH₃OH=10/1) to provideN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-2-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-2H-tetrazole-5-carboxamide(20.2 mg, yield: 23%) as a white solid. ESI-MS [M+H]⁺: 448.1. Purity:98.48%. ¹H NMR (400 MHz, DMSO): δ 9.44 (t, J=5.8 Hz, 1H), 8.36 (s, 1H),8.31-8.30 (m, 2H), 7.94 (s, 1H), 7.83 (s, 1H), 7.38 (d, J=9.3 Hz, 1H),7.01 (dd, J=9.4, 1.6 Hz, 1H), 6.65 (dd, J=7.4, 2.0 Hz, 1H), 6.06 (s,2H), 4.64 (d, J=5.9 Hz, 2H), 1.96-1.89 (m, 1H), 1.02-0.84 (m, 2H),0.83-0.57 (m, 2H).

Example 111

Synthesis of 2-(azidomethyl)-6-cyclopropylimidazo[1,2-b]pyridazine

To a solution of 2-(chloromethyl)-6-cyclopropylimidazo[1,2-b]pyridazine(900 mg, 4.33 mmol) in dry DMF (5 mL) was added NaN₃ (631 mg, 9.71mmol). The reaction mixture was stirred at RT for 2 h. Water (30 mL) wasadded and the mixture was extracted with EtOAc (30 mL×3). The combinedorganic layers were washed with brine, dried over Na₂SO₄ andconcentrated to give the crude product, which was purified by flashchromatography with silica gel (EtOAc/PE=40%) to give2-(azidomethyl)-6-cyclopropylimidazo[1,2-b]pyridazine (735 mg, yield:79%) as dark-red oil. ESI-MS [M+H]⁺: 215.2.

Synthesis of Ethyl1-((6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate

To a solution of 2-(azidomethyl)-6-cyclopropylimidazo[1,2-b]pyridazine(730 mg, 3.41 mmol) and ethyl propiolate (501.42 mg, 5.11 mmol) in amixture of t-BuOH/H₂O (5 mL/5 mL) was added CuSO₄ (543.85 mg, 3.41 mmol)and sodium ascorbate (675.05 mg, 3.41 mmol). Then the mixture wasstirred at RT for 2 h. The mixture was concentrated and purified byflash silica gel chromatography (EtOAc/PE=10%) to give ethyl1-((6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(600 mg, yield: 56.44%) as a red solid. ESI-MS [M+H]⁺: 313.2.

Synthesis of1-((6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicAcid

To a solution of ethyl1-((6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(100 mg, 0.32 mmol) in a mixture of THF/EtOH/H₂O (2 mL/2 mL/1 mL) wasadded LiOH (15.33 mg, 0.64 mmol). The mixture was heated to 50° C. for 2h. Then the mixture was freeze-dried to give1-((6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (110 mg, crude) as a white solid which was used into next stepwithout purification. ESI-MS [M+H]⁺: 285.1.

Synthesis ofN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(I-111)

To a solution of1-((6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (30 mg, crude from last step) in DMF (2 mL) was added EDCI (30.35mg, 0.158 mmol), HOBT (21.39 mg, 0.158 mmol), DIPEA (68.20 mg, 0.528mmol) and (7-chloroimidazo[1,5-a]pyridin-1-yl)methanamine (19.17 mg,0.106 mmol). Then the mixture was stirred at RT for 16 h. Water (15 mL)was added and the mixture was extracted with ethyl acetate (25 mL×4).The combined organic layers were concentrated to give the crude product,which was purified by prep-TLC to giveN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(28 mg, yield: 59.09%) as a white solid. ESI-MS [M+H]⁺: 448.2. Purity:96%. ¹H NMR (400 MHz, DMSO): δ 8.91 (t, J=5.8 Hz, 1H), 8.57 (s, 1H),8.33-8.27 (m, 2H), 8.19 (s, 1H), 7.93 (d, J=9.4 Hz, 1H), 7.83 (s, 1H),7.10 (d, J=9.4 Hz, 1H), 6.67-6.62 (m, 1H), 5.75 (s, 2H), 4.61 (d, J=5.9Hz, 2H), 2.22-2.13 (m, 1H), 1.12-1.02 (m, 2H), 1.00-0.94 (m, 2H).

Example 112

Synthesis of2-(azidomethyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-carbonitrile

To a mixture of2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-carbonitrile (100mg, 0.43 mmol) in dry DMF (2 mL) was added NaN₃ (39 mg, 0.65 mmol). Themixture was stirred at 25° C. for 3 h. Then H₂O (20 mL) was added andextracted with EtOAc (20 mL×3). The combined organic layers were washedwith brine, dried over Na₂SO₄ and concentrated to give the crude, whichwas purified by prep-TLC (EA/PE=3/2) to give2-(azidomethyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-carbonitrile (70mg, yield: 68%) as a yellow solid. ESI-MS [M+H]⁺: 239.2.

Synthesis of Ethyl1-((8-cyano-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate

To a mixture of2-(azidomethyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-carbonitrile (70mg, 0.29 mmol), CuSO₄ (24 mg, 0.15 mmol), sodium ascorbate (30 mg, 0.15mmol) in t-BuOH/H₂O (3/3 mL) was added ethyl propiolate (43 mg, 0.44mmol). The mixture was stirred at 25° C. for 16 h and then concentratedto give the crude product. PE/EA (10 mL/1 mL) was added, stirred at 25°C. for 5 min, and a solid was filtered and washed with PE to give ethyl1-((8-cyano-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(95 mg, yield: 96%) as a yellow solid, which was used into next stepwithout purification. ESI-MS [M+H]⁺: 337.2.

Synthesis of1-((8-cyano-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicAcid

To a mixture of ethyl1-((8-cyano-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(95 mg, 0.28 mmol) in THF/H₂O (4 mL/2 mL) was added NaOH (34 mg, 0.85mmol). The mixture was stirred at 25° C. for 16 h. The pH of the mixturewas adjusted to 5 with 1 M HCl, then extracted with EtOAc (50 mL×3). Thecombined organic layers were washed with brine, dried over Na₂SO₄ andconcentrated to give1-((8-cyano-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (70 mg, yield: 80%) as a grey solid. ESI-MS [M+H]⁺: 309.2.

Synthesis ofN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((8-cyano-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(I-112)

To a mixture of1-((8-cyano-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (60 mg, 0.19 mmol), (7-chloroimidazo[1,5-a]pyridin-1-yl)methanamine(42 mg, 0.23 mmol), HOBT (54 mg, 0.4 mmol), EDCI (75 mg, 0.4 mmol) inDMF (3 mL) was added DIPEA (126 mg, 0.98 mmol). The mixture was stirredat 25° C. for 16 h. Water (20 mL) was added, extracted with EtOAc (20mL×3). The combined organic layers were washed with brine, dried overNa₂SO₄, filtered and concentrated to give the crude product, which waspurified by prep-HPLC to giveN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((8-cyano-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(53.7 mg, yield: 58%) as a yellow solid. ESI-MS [M+H]+: 472.1. Purity:99.54%. ¹H NMR (400 MHz, DMSO): δ 8.94 (s, 1H), 8.69-8.60 (m, 2H),8.31-8.30 (m, 2H), 7.99 (s, 1H), 7.84-7.80 (m, 2H), 6.65 (s, 1H), 5.81(s, 2H), 4.63 (s, 2H), 1.98-1.97 (m, 1H), 0.96-0.95 (m, 2H), 0.76-0.75(m, 2H).

Example 113

Synthesis of 4-methoxybenzyl1-(4-methoxybenzyl)-1H-pyrazole-4-carboxylate

A solution of 1H-pyrazole-4-carboxylic acid (6 g, 53.53 mmol), PMBCl(18.4 g, 117.76 mmol) and Cs₂CO₃ (52.3 mg, 160.59 mmol) in DMF (100 mL)was stirred at RT for 16 h. The reaction mixture was poured into H₂O(600 mL) and extracted with EtOAc (500 mL×3). The combined organiclayers were washed with brine (200 mL), dried over Na₂SO₄ andconcentrated. The crude product was purified by silica gelchromatography (EA/PE=1/5) to give 4-methoxybenzyl1-(4-methoxybenzyl)-1H-pyrazole-4-carboxylate (9.8 g, yield: 52%) as awhite solid. ESI-MS [M+H]⁺: 353.2.

Synthesis of 4-methoxybenzyl5-formyl-1-(4-methoxybenzyl)-1H-pyrazole-4-carboxylate

To a solution of 4-methoxybenzyl1-(4-methoxybenzyl)-1H-pyrazole-4-carboxylate (9.8 g, 27.81 mmol) in THF(100 mL) was added dropwise of LDA (41.7 mL, 41.7 mmol) at −78° C. over10 min. After stirring for 5 min DMF (12.2 g, 167.86 mmol) was added.The resulting mixture was stirred at −78° C. for another 10 min. Thereaction was quenched with saturated NH₄Cl aqueous (100 mL) andextracted with EtOAc (200 mL×3). The combined organic layers were washedwith brine, dried over Na₂SO₄, concentrated and purified by silica gelchromatography (EA/PE=1/3) to give 4-methoxybenzyl5-formyl-1-(4-methoxybenzyl)-1H-pyrazole-4-carboxylate (4.9 g, yield:44%) as a white solid. ESI-MS [M+H]⁺: 403.1.

Synthesis of 4-methoxybenzyl(E)-5-(3-ethoxy-3-oxoprop-1-en-1-yl)-1-(4-methoxybenzyl)-1H-pyrazole-4-carboxylate

To a solution of 4-methoxybenzyl5-formyl-1-(4-methoxybenzyl)-1H-pyrazole-4-carboxylate (4.9 g, 12.88mmol) in DCM (100 mL) was added ethyl2-(triphenyl-15-phosphanylidene)acetate (5.83 g, 16.74 mmol) in portionsat 0° C. The mixture was stirred at RT for 16 h. Water (200 mL) wasadded and the mixture was extracted with DCM (200 mL×3). The combinedorganic layers were concentrated to give the crude product, which waspurified by silica gel chromatography (EA/PE=1/3) to give4-methoxybenzyl(E)-5-(3-ethoxy-3-oxoprop-1-en-1-yl)-1-(4-methoxybenzyl)-1H-pyrazole-4-carboxylate(5.7 g, 98%) as a yellow solid. ESI-MS [M+H]⁺: 451.2.

Synthesis of 4-methoxybenzyl5-(2-(ethoxycarbonyl)cyclopropyl)-1-(4-methoxybenzyl)-1H-pyrazole-4-carboxylate

To a suspension of NaH (102 mg, 2.68 mmol) in DMSO (10 mL) was addedtrimethylsulfoxonium iodide (967 mg, 4.39 mmol) at RT. The mixture wasstirred at RT for 10 mins. Then a solution of 4-methoxybenzyl(E)-5-(3-ethoxy-3-oxoprop-1-en-1-yl)-1-(4-methoxybenzyl)-1H-pyrazole-4-carboxylate(1.1 g, 2.44 mmol) in DMSO/THF (6 mL, 1/1 (v/v)) was added. Theresulting mixture was stirred at RT for 16 h. The reaction mixture wasquenched with NH₄Cl aqueous (100 mL) and extracted with EtOAc (100mL×3). The combined organic layers were washed with brine, dried overNa₂SO₄, concentrated and purified by silica gel chromatography(EA/PE=1/2) to give 4-methoxybenzyl5-(2-(ethoxycarbonyl)cyclopropyl)-1-(4-methoxybenzyl)-1H-pyrazole-4-carboxylate(1.1 g, yield: 97%) as a yellow solid. ESI-MS [M+H]⁺: 465.2.

Synthesis of 3-(2-(ethoxycarbonyl)cyclopropyl)-1H-pyrazole-4-carboxylicAcid

A solution of 4-methoxybenzyl5-(2-(ethoxycarbonyl)cyclopropyl)-1-(4-methoxybenzyl)-1H-pyrazole-4-carboxylate(1.1 g, 2.37 mmol) in TFA (10 mL) was stirred at 50° C. for 16 h. Thereaction mixture was concentrated and diluted in H₂O (50 mL) and the pHwas adjusted to 6-7 by adding saturated NaHCO₃ and then extracted withEtOAc (100 mL×3). The combined organic layers were washed with brine,dried over Na₂SO₄, concentrated and purified by silica gelchromatography (EA/PE=1/3) to give3-(2-(ethoxycarbonyl)cyclopropyl)-1H-pyrazole-4-carboxylic acid (230 mg,yield: 43%) as a yellow solid. ESI-MS [M+H]⁺: 225.1.

Synthesis of Ethyl2-(4-(((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-pyrazol-3-yl)cyclopropane-1-carboxylate

A mixture of 3-(2-(ethoxycarbonyl)cyclopropyl)-1H-pyrazole-4-carboxylicacid (230 mg, 1.03 mmol),(7-chloroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride (337 mg,1.545 mmol), HATU (431 mg, 1.133 mmol) and DIPEA (399 mg, 3.09 mmol) inDMF (10 mL) was stirred at RT for 16 h. The reaction mixture was pouredinto H₂O (120 mL) and extracted with EtOAc/THF (80 mL×3, 5/1 (v/v)). Thecombined organic layers were washed with brine, dried over Na₂SO₄,concentrated and purified by silica gel chromatography (DCM/MeOH=20/1)to give ethyl2-(4-(((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-pyrazol-3-yl)cyclopropane-1-carboxylate(150 mg, yield: 38%) as a yellow solid. ESI-MS [M+H]⁺: 388.1.

Synthesis of Ethyl2-(4-(((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazol-3-yl)cyclopropane-1-carboxylate(I-113)

A mixture of ethyl2-(4-(((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-pyrazol-3-yl)cyclopropane-1-carboxylate(150 mg, 0.387 mmol),2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine (96 mg, 0.464 mmol)and Cs₂CO₃ (189 mg, 0.581 mmol) in DMF (6 mL) was stirred at 50° C. for5 h. Water (50 mL) was added and extracted with EtOAc (50 mL×3). Thecombined organic layers were washed with brine, dried over Na₂SO₄,concentrated and purified by silica gel chromatography (DCM/MeOH=8/1) togive ethyl2-(4-(((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazol-3-yl)cyclopropane-1-carboxylate(110 mg, yield: 51%) as a yellow solid. ESI-MS [M+H]⁺: 558.2. Purity:95.76%. ¹H NMR (400 MHz, DMSO): δ 8.45 (t, J=5.6 Hz, 1H), 8.35-8.28 (m,3H), 8.14 (s, 1H), 7.75 (m, 2H), 7.39 (d, J=9.3 Hz, 1H), 6.99 (dd,J=9.4, 1.7 Hz, 1H), 6.64 (dd, J=7.4, 2.1 Hz, 1H), 5.27 (s, 2H), 4.53 (d,J=5.7 Hz, 2H), 4.08 (q, J=7.0 Hz, 2H), 3.22-3.16 (m, 1H), 2.01-1.95 (m,1H), 1.91 (m, 1H), 1.41-1.32 (m, 2H), 1.18 (t, J=7.1 Hz, 3H), 0.94-0.88(m, 2H), 0.69-0.63 (m, 2H).

Example 114

Synthesis ofN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(2-oxopyrrolidin-1-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(I-114)

A mixture of1-(2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)pyrrolidin-2-one(25 mg, 0.087 mmol),N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide(26 mg, 0.095 mmol) and Cs₂CO₃ (70 mg, 0.216 mmol) in DMF (3 mL) wasstirred at RT for 3 h. The reaction was quenched with H₂O (30 mL) wasadded and extracted with EtOAc (30 mL×3). The combined organic layerswere washed with brine, dried over Na₂SO₄ and concentrated in vacuo togive the crude, which was purified by prep-HPLC to giveN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(2-oxopyrrolidin-1-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(16.2 mg, yield: 35%) as a white solid. ESI-MS [M+H]⁺: 529.2. Purity:99.4%. ¹H NMR (400 MHz, DMSO): δ 8.58 (t, J=5.7 Hz, 1H), 8.31-8.30 (m,2H), 8.26 (d, J=1.2 Hz, 1H), 8.19 (s, 1H), 7.89 (s, 1H), 7.78 (d, J=1.2Hz, 1H), 7.71 (s, 1H), 7.16 (d, J=1.5 Hz, 1H), 6.65 (dd, J=7.5, 2.1 Hz,1H), 5.41 (s, 2H), 4.55 (d, J=5.7 Hz, 2H), 4.10 (t, J=7.1 Hz, 2H), 2.45(t, J=8.2 Hz, 2H), 2.14-2.03 (m, 2H), 1.95-1.88 (m, 1H), 0.98-0.89 (m,2H), 0.68-0.59 (m, 2H).

Example 115

Synthesis of Ethyl1-(2-((4-(((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-pyrazol-1-yl)methyl)imidazo[1,2-a]pyridin-8-yl)cyclopropane-1-carboxylate(I-115)

A mixture of1-((8-(1-(ethoxycarbonyl)cyclopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylicacid (108 mg, 0.27 mmol),(7-chloroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride (89 mg,0.41 mmol), DIPEA (174 mg, 1.35 mmol) and HATU (205 mg, 0.54 mmol) inDMF (3 mL) was stirred at RT for 3 h. The reaction was diluted with H₂O(30 mL) and extracted with EtOAc (30 mL×3). The combined organic layerswere washed with brine, dried over Na₂SO₄ and concentrated in vacuo togive the crude, which was purified by prep-HPLC to give ethyl1-(2-((4-(((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-pyrazol-1-yl)methyl)imidazo[1,2-a]pyridin-8-yl)cyclopropane-1-carboxylate(13.4 mg, yield: 8.9%) as a white solid. ESI-MS [M+H]⁺: 558.2. Purity:98.1%. ¹H NMR (400 MHz, MeOD): δ 8.25 (s, 1H), 8.15 (d, J=7.5 Hz, 1H),8.09 (d, J=2.1 Hz, 2H), 7.91 (s, 1H), 7.73 (s, 1H), 7.67 (s, 1H), 7.02(d, J=1.3 Hz, 1H), 6.61 (dd, J=7.4, 1.6 Hz, 1H), 5.44 (s, 2H), 4.67 (s,2H), 3.97 (q, J=7.1 Hz, 2H), 1.91 (ddd, J=13.5, 8.5, 5.2 Hz, 1H), 1.68(dd, J=7.2, 4.2 Hz, 2H), 1.25 (dd, J=7.2, 4.2 Hz, 2H), 1.05-0.86 (m,5H), 0.75-0.62 (m, 2H).

Example 116

Synthesis of1-(2-((4-(((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-pyrazol-1-yl)methyl)imidazo[1,2-a]pyridin-8-yl)cyclopropane-1-carboxylicacid (I-116)

To a mixture of ethyl1-(2-((4-(((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-pyrazol-1-yl)methyl)imidazo[1,2-a]pyridin-8-yl)cyclopropane-1-carboxylate(50 mg, 0.09 mmol) in EtOH (2 mL) was added NaOH (6.4 mg, 0.16 mmol) inH₂O (1 mL). The mixture was stirred at RT for 3 h. The pH of the residuewas adjusted to 4 by adding 1 M HCl solution. The mixture was thenconcentrated and purified by prep-HPLC to give the1-(2-((4-(((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-pyrazol-1-yl)methyl)imidazo[1,2-a]pyridin-8-yl)cyclopropane-1-carboxylicacid (21.6 mg, yield: 45%) as a white solid. ESI-MS [M+H]⁺: 530.2.Purity: 96.5%. ¹H NMR (400 MHz, MeOD): δ 8.25 (s, 1H), 8.16 (d, J=7.5Hz, 1H), 8.11 (s, 2H), 7.91 (s, 1H), 7.73 (s, 1H), 7.67 (s, 1H), 7.09(d, J=1.5 Hz, 1H), 6.62 (dd, J=7.5, 2.0 Hz, 1H), 5.46 (s, 2H), 4.67 (s,2H), 1.93 (ddd, J=13.5, 8.4, 5.1 Hz, 1H), 1.72 (dd, J=7.1, 4.1 Hz, 2H),1.25 (dd, J=7.2, 4.2 Hz, 2H), 1.01-0.91 (m, 2H), 0.78-0.66 (m, 2H).

Example 117

Synthesis of benzyl1-((8-(1-(hydroxymethyl)cyclopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate

To a mixture of benzyl1-((8-(1-(ethoxycarbonyl)cyclopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate(266 mg, 0.6 mmol) in THF/MeOH (5 mL/0.5 mL) was added LiBH₄ (136 mg, 6mmol) at 0° C. The mixture was stirred at 0° C. for 3 h. The reactionwas quenched with H₂O (20 mL) and extracted with EtOAc (50 mL×3). Thecombined organic layers were washed with brine, dried over Na₂SO₄, andconcentrated in vacuo to give the crude which was purified by prep-TLC(DCM/MeOH: 10/1) to give benzyl1-((8-(1-(hydroxymethyl)cyclopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate(94 mg, yield: 38%) as a white solid. ESI-MS [M+H]⁺: 403.1.

Synthesis of1-((8-(1-(hydroxymethyl)cyclopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylicAcid

To a mixture of benzyl1-((8-(1-(hydroxymethyl)cyclopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate(94 mg, 0.23 mmol) in MeOH (3 mL) was added Pd/C (30 mg, 0.3 mmol). Themixture was stirred at RT for 3 h under H₂. The reaction was filteredand concentrated in vacuo to give1-((8-(1-(hydroxymethyl)cyclopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylicacid (70 mg, yield: 97%) as a white solid, which was used into the nextstep without purification. ESI-MS [M+H]⁺: 313.1.

Synthesis ofN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((8-(1-(hydroxymethyl)cyclopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(I-117)

A mixture of1-((8-(1-(hydroxymethyl)cyclopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylicacid (70 mg, 0.2 mmol), (7-chloroimidazo[1,5-a]pyridin-1-yl)methanaminehydrochloride (87.2 mg, 0.4 mmol), DIPEA (129 mg, 1 mmol) and HATU (152mg, 0.4 mmol) in DMF (3 mL) was stirred at RT for 3 h. The reaction wasdiluted with H₂O (30 mL) and extracted with EtOAc (30 mL×3). Thecombined organic layers were washed with brine, dried over Na₂SO₄ andconcentrated in vacuo to give the crude, which was purified withprep-HPLC to giveN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((8-(1-(hydroxymethyl)cyclopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(26 mg, yield: 23%) as a white solid. ESI-MS [M+H]⁺: 516.2. Purity:97.0%. ¹H NMR (400 MHz, MeOD): δ 8.24 (s, 1H), 8.17-8.09 (m, 2H), 8.04(s, 1H), 7.90 (d, J=9.6 Hz, 1H), 7.72 (s, 1H), 7.65 (s, 1H), 6.99 (d,J=1.3 Hz, 1H), 6.60 (dd, J=7.5, 1.9 Hz, 1H), 5.46 (s, 2H), 4.67 (s, 2H),3.71 (s, 2H), 1.89 (ddd, J=13.4, 8.5, 5.1 Hz, 1H), 0.98-0.84 (m, 6H),0.72-0.64 (m, 2H).

Example 118

Synthesis of1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-((7-vinylimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide(I-118)

A mixture ofN-((7-bromoimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(50 mg, 0.16 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (17mg, 0.11 mmol), tetrakis(triphenylphosphine)palladium(0) (23 mg, 0.02mmol) in dioxane/H₂O (2 mL/0.5 mL) was stirred at 100° C. for 2 h. Water(20 mL) was added and extracted with ethyl acetate (30 mL*3). Thecombined organic layers were washed with brine, dried over anhydroussodium sulfate and concentrated. The residue was purified by Prep-HPLCto give1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-((7-vinylimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide(34 mg, yield: 75%) as a white solid. ESI-MS [M+H]⁺: 438.2. Purity:93.19%. ¹H NMR (400 MHz, DMSO) δ 8.52 (t, J=5.5 Hz, 1H), 8.32 (s, 1H),8.27 (s, 1H), 8.25-8.17 (m, 2H), 7.86 (s, 1H), 7.71 (s, 1H), 7.55 (s,1H), 7.39 (d, J=9.3 Hz, 1H), 7.02-6.96 (m, 1H), 6.94-6.88 (m, 1H),6.68-6.57 (m, 1H), 5.77 (d, J=17.5 Hz, 1H), 5.38 (s, 2H), 5.26 (d,J=11.0 Hz, 1H), 4.57 (d, J=5.6 Hz, 2H), 1.96-1.87 (m, 1H), 0.94-0.88 (m,2H), 0.69-0.63 (m, 2H).

Example 119

Synthesis ofN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(3-hydroxy-3-methylbutyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(I-119)

To a solution of ethyl3-(2-((4-(((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-pyrazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)propanoate(35 mg, 0.064 mmol) in THF (3 mL) was added MeMgBr (0.32 mL, 1.0 Msolution in THF, 0.32 mmol) slowly 0° C. The reaction was stirred at 0°C. for 2 h., quenched with aqueous NH₄Cl (15 mL), and extracted withEtOAc (30 mL×3). The combined organic layers were washed with brine,dried over Na₂SO₄, and concentrated in vacuo to give the crude product,which was purified by prep-TLC (DCM/MeOH=10/1) to giveN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(3-hydroxy-3-methylbutyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(20 mg, yield: 58.8%) as a white solid. ESI-MS [M+H]⁺: 532.2. Purity:95.7%. ¹H NMR (400 MHz, DMSO): δ 8.60 (s, 1H), 8.32-8.30 (m, 2H), 8.18(d, J=18.5 Hz, 2H), 7.89 (s, 1H), 7.79 (s, 1H), 7.63 (s, 1H), 6.80 (s,1H), 6.65 (d, J=5.5 Hz, 1H), 5.41 (s, 2H), 4.56 (s, 2H), 4.31 (s, 1H),2.87 (s, 2H), 2.00-1.85 (m, 1H), 1.75 (s, 2H), 1.16 (s, 6H), 1.00-0.85(m, 2H), 0.72-0.63 (m, 2H).

Example 120

Synthesis of2-(4-(((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazol-3-yl)cyclopropane-1-carboxylicAcid (I-120)

To a solution of ethyl2-(4-(((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazol-3-yl)cyclopropane-1-carboxylate(80 mg, 0.143 mmol) in MeOH/THF/H₂O (3 mL/3 mL/2 mL) was added lithiumhydroxide monohydrate (30 mg, 0.717 mmol). The mixture was stirred at40° C. for 1 h. Most of the solvent was removed and the residue wasdiluted with H₂O (10 mL). The pH of the mixture was adjusted to 4-5 byadding HCl aqueous (1 M) and extracted with DCM/MeOH (30 mL×3, 10/1).The combined organic layers were washed with brine, dried over Na₂SO₄,concentrated and purified by prep-TLC (DCM/MeOH=10/1) to give2-(4-(((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazol-3-yl)cyclopropane-1-carboxylicacid (6 mg, yield: 8%) as a yellow solid. ESI-MS [M+H]⁺: 530.2. Purity:95.64%. ¹H NMR (400 MHz, DMSO): δ 12.16 (s, 1H), 8.43 (t, J=5.6 Hz, 1H),8.39-8.26 (m, 3H), 8.13 (s, 1H), 7.75 (m, 2H), 7.39 (d, J=9.3 Hz, 1H),7.00 (dd, J=9.4, 1.7 Hz, 1H), 6.64 (dd, J=7.5, 2.1 Hz, 1H), 5.27 (s,2H), 4.60-4.48 (m, 2H), 3.21-3.13 (m, 1H), 1.96-1.85 (m, 2H), 1.36-1.29(m, 2H), 0.91 (m, 2H), 0.72-0.63 (m, 2H).

Example 121

Synthesis of Methyl2-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-2H-1,2,3-triazole-4-carboxylate

To the mixture of 2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine(200 mg, 0.97 mmol) in dry DMF (5 mL) was added methyl2H-1,2,3-triazole-4-carboxylate (135 mg, 1.06 mmol) and Cs₂CO₃ (949 mg,2.91 mmol). The mixture was stirred at 25° C. for 16 h. Then H₂O (30 mL)was added and extracted with EtOAc (50 mL×3). The combined organiclayers were washed with brine, dried over Na₂SO₄, filtered andconcentrated to give the crude product, which was purified by prep-TLC(DCM/MeOH=10/1) to give methyl2-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-2H-1,2,3-triazole-4-carboxylate(90 mg, yield: 31%) as a yellow solid. ESI-MS [M+H]⁺: 298.1.

Synthesis of2-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-2H-1,2,3-triazole-4-carboxylicAcid

To a mixture of methyl2-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-2H-1,2,3-triazole-4-carboxylate(90 mg, 0.3 mmol) in THF/H₂O (3 mL/2 mL) was added NaOH (36 mg, 0.9mmol). The mixture was stirred at 25° C. for 16 h and the pH of themixture was adjusted to 5 by adding 1 M HCl. The mixture was thenextracted with EtOAc (50 mL×3). The combined organic layers were washedwith brine, dried over Na₂SO₄ and concentrated to give2-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-2H-1,2,3-triazole-4-carboxylicacid (80 mg, yield: 93%) as a yellow solid. ESI-MS [M+H]⁺: 284.0.

Synthesis ofN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-2-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-2H-1,2,3-triazole-4-carboxamide(I-121)

To a mixture of2-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-2H-1,2,3-triazole-4-carboxylicacid (60 mg, 0.21 mmol), (7-chloroimidazo[1,5-a]pyridin-1-yl)methanaminehydrochloride (54 mg, 0.25 mmol), HOBT (57 mg, 0.42 mmol), EDCI (81 mg,0.42 mmol) in DMF (5 mL) was added DIPEA (135 mg, 1.04 mmol). Themixture was stirred at 25° C. for 16 h. Water (30 mL) was added andextracted with EtOAc (30 mL×3). The combined organic layers were washedwith brine, dried over Na₂SO₄, filtered and concentrated to give thecrude product, which was purified by prep-TLC (DCM/MeOH=10/1) to giveN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-2-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-2H-1,2,3-triazole-4-carboxamide(39.1 mg, yield: 41%) as a white solid. ESI-MS [M+H]⁺: 447.1. Purity:99.57%. H NMR (400 MHz, DMSO): δ 8.90 (t, J=5.8 Hz, 1H), 8.31-8.30 (m,3H), 8.15 (s, 1H), 7.83-7.82 (m, 1H), 7.77 (s, 1H), 7.39=7.36 (m, 1H),7.00-6.98 (m, 1H), 6.66-6.64 (m, 1H), 5.74 (s, 2H), 4.60 (d, J=5.9 Hz,2H), 1.95-1.88 (m, 1H), 0.94-0.89 (m, 2H), 0.68-0.64 (m, 2H).

Example 122

Synthesis of3-(2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)oxetan-3-ol

To a solution of 3-(2-amino-5-cyclopropylpyridin-3-yl)oxetan-3-ol (800mg, 3.88 mmol) in EtOH (10 mL) was added 1,3-dichloropropan-2-one (1.48g, 11.6 mmol) at RT. The resulting reaction mixture was stirred at 85°C. for 2 h. Water (30 mL) was added and the pH was adjusted to 8 byadding saturated NaHCO₃ solution. The mixture was then extracted withEtOAc (30 mL×3). The combined organic layers were washed with brine,dried over Na₂SO₄ and concentrated in vacuo to give the crude product,which was purified by silica gel chromatography (PE/EtOAc=1/1) to givethe3-(2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)oxetan-3-ol(900 mg, yield: 83%) as a light yellow oil. ESI-MS [M+H]⁺: 279.2.

Synthesis ofN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(3-hydroxyoxetan-3-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(I-122)

To a solution3-(2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)oxetan-3-ol(90 mg, 0.33 mmol) in DMF (5 mL) was addedN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide(60 mg, 0.22 mmol) and Cs₂CO₃ (215 mg, 0.66 mmol) at RT. The resultingreaction mixture was stirred at RT for 12 h. Water (30 mL) was added andextracted with EtOAc (50 mL×3). The combined organic layers were washedwith brine, dried over Na₂SO₄ and concentrated in vacuo to give thecrude product, which was purified with prep-TLC (DCM/MeOH=10/1) to givetheN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(3-hydroxyoxetan-3-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(20 mg, yield: 12%) as a white solid. ESI-MS [M+H]⁺: 518.1. Purity:97.8%. ¹H NMR (400 MHz, DMSO): δ 8.59 (s, 1H), 8.33-8.26 (m, 3H), 8.20(s, 1H), 7.90 (s, 1H), 7.81-7.75 (m, 1H), 7.66 (s, 1H), 7.06 (d, J=1.6Hz, 1H), 6.67-6.62 (m, 1H), 6.44 (s, 1H), 5.43 (s, 2H), 5.23 (d, J=6.5Hz, 2H), 4.63 (d, J=6.5 Hz, 2H), 4.55 (d, J=5.7 Hz, 2H), 1.98-1.91 (m,1H), 0.95-0.88 (m, 2H), 0.70-0.64 (m, 2H).

Example 123

Synthesis ofN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carbothioamide

A mixture ofN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(400 mg, 0.9 mmol) and Lawesson's reagent (544 mg, 1.35 mmol) in CH₃CN(10 mL) was stirred at 90° C. for 16 h. The reaction mixture was cooledto RT and then filtered to provide the crude product (400 mg, yield:96.6%) as a white solid which was used in the next step withoutpurification. ESI-MS [M+H]⁺: 462.1.

Synthesis of MethylN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carbimidothioate

To a solution ofN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carbothioamide(440 mg, 0.95 mmol) in DMF (5 mL) was added NaH (76 mg, 1.9 mmol) andthe reaction was stirred at 0° C. for 30 min. Then MeI (203 mg, 1.43mmol) was added. The resulting reaction mixture was stirred at RT for 2h. Water (30 mL) was added and extracted with EtOAc (30 mL×3). Thecombined organic layers were washed with brine, dried over Na₂SO₄, andconcentrated to give methylN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carbimidothioate(250 mg, crude), which was used in the next step without furtherpurification. ESI-MS [M+H]⁺: 476.2.

Synthesis ofN′-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-N-cyano-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboximidamide(I-123)

A mixture of methylN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carbimidothioate(250 mg, 0.53 mmol) and NH₂CN (88 mg, 2.1 mmol) in DMF (3 mL) wasstirred at 90° C. for 2 h. The reaction mixture was diluted with H₂O (30mL) and extracted with EtOAc (30 mL×3). The combined organic layers werewashed with brine, dried over Na₂SO₄, and concentrated. The crudeproduct was purified by prep-TLC (DCM/MeOH=10/1) to provideN′-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-N-cyano-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboximidamide(5 mg, yield: 2%). ESI-MS [M+H]⁺: 470.2. Purity: 90.02%. ¹H NMR (400MHz, DMSO): δ 8.45 (s, 1H), 8.30 (s, 1H), 8.21-8.18 (m, 2H), 8.12 (s,1H), 7.77-7.74 (m, 2H), 7.45 (d, J=8 Hz, 1H), 7.14 (t, J=12.0 Hz, 1H),6.67 (m, 1H), 5.52 (s, 2H), 4.76 (s, 2H), 1.96-1.92 (m, 1H), 0.99-0.96(m, 2H), 0.73-0.70 (s, 2H).

Example 124

Synthesis of 2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine

A mixture of 5-cyclopropylpyridin-2-amine (3.3 g, 25 mmol, 1.0 equiv)and 1,3-dichloropropan-2-one (12.4 g, 99 mmol, 4.0 equiv) in EtOH (60mL) was stirred at 85° C. for 16 h. The solvent was removed in vacuo.Water (100 mL) was added and extracted with EtOAc (200 mL×3). Thecombined organic layers were concentrated and purified by silica gelchromatography (PE:EA=5:3) to provide2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine (1.8 g, yield:34.9%). ESI-MS [M+H]⁺: 207.1.

Synthesis of (6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methanol

A solution of 2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine (1.8g, 8.7 mmol) and NaHCO₃ (5 mL, aq., sat.) in THF (10 mL) was stirred at100° C. for 16 h. Then Water (50 mL) was added and the mixture wasextracted with EtOAc (50 mL×3). The combined organic layers wereconcentrated to provide(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methanol (1.45 g, crude) whichwas used in the next step without further purification. ESI-MS [M+H]⁺:189.1.

Synthesis of 6-cyclopropylimidazo[1,2-a]pyridine-2-carbaldehyde

A mixture of (6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methanol (1.45 g,crude from last step) and IBX (4.3 g, 15.4 mmol, 2.0 equiv.) in EtOAc(50 mL) was refluxed at 80° C. for 16 h. Then H₂O (50 mL) was added andextracted by EtOAc (50 mL×3). The combined organic layers were washedwith brine, dried over Na₂SO₄, and concentrated to give the crudeproduct, which was purified by silica gel chromatography (PE:EA=2:1) toprovide 6-cyclopropylimidazo[1,2-a]pyridine-2-carbaldehyde (780 mg,yield: 48% in 2 steps). ESI-MS [M+H]⁺: 187.1

Synthesis of 1-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)ethan-1-ol

To a solution of 6-cyclopropylimidazo[1,2-a]pyridine-2-carbaldehyde (750mg, 4.0 mmol) in THF (10 mL) was added MeMgBr (2 mL, 6.0 mmol) dropwiseat 0° C. The reaction mixture was stirred at 0° C. for 3 h. Thenreaction mixture was quenched with saturated NH₄Cl solution (10 mL) andextracted by by EtOAc (50 mL×3). The combined organic layers were washedwith brine, dried over Na₂SO₄, and concentrated to give the crudeproduct, which was purified by silica gel chromatography (DCM:MeOH=10:1)to give 1-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)ethan-1-ol (725 mg,yield: 89.7%). ESI-MS [M+H]⁺: 203.2.

Synthesis of 1-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)ethylmethanesulfonate

A mixture of 1-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)ethan-1-ol (725mg, 3.5 mmol), DIPEA (1.35 g, 10.5 mmol) and MsCl (519 mg, 4.55 mmol) inDCM (20 mL) was stirred at RT for 2 h. Water (20 mL) was added andextracted with EtOAc (50 mL×3). The combined organic layers were washedwith brine, dried over Na₂SO₄, filtered and concentrated to give thecrude compound (980 mg, crude), which was used into the next stepdirectly.

Synthesis of 2-(1-azidoethyl)-6-cyclopropylimidazo[1,2-a]pyridine

A mixture of 1-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)ethylmethanesulfonate (980 mg, crude form last step) and NaN₃ (680 mg, 10.5mmol) in DMF (5 mL) was stirred at RT for 2 h. Water (30 mL) was addedand extracted with EtOAc (50 mL×3). The combined organic layers werewashed with brine, dried over Na₂SO₄, and concentrated to give the crudeproduct which was purified by prep-TLC (PE:EA=2:1) to give2-(1-azidoethyl)-6-cyclopropylimidazo[1,2-a]pyridine (225 mg, yield: 28%in 2 steps) as a yellow solid. ESI-MS [M+H]⁺: 228.2.

Synthesis of Ethyl1-(1-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)ethyl)-1H-1,2,3-triazole-4-carboxylate

A mixture of 2-(1-azidoethyl)-6-cyclopropylimidazo[1,2-a]pyridine (225mg, 0.99 mmol), ethyl propiolate (107.0 mg, 1.09 mmol), CuSO₄ (173 mg,1.09 mmol) and sodium ascorbate (200 mg, 0.99 mmol) in a mixture oft-BuOH (10 mL) and H₂O (10 mL) was stirred at RT for 16 h. Solidprecipitated and filtered to give ethyl1-(1-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)ethyl)-1H-1,2,3-triazole-4-carboxylate(250 mg, yield: 77%) as a yellow solid. ESI-MS [M+H]⁺: 326.2.

Synthesis of1-(1-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)ethyl)-1H-1,2,3-triazole-4-carboxylicAcid

A mixture of ethyl1-(1-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)ethyl)-1H-1,2,3-triazole-4-carboxylate(250 mg, 0.77 mmol) and NaOH (111 mg, 2.77 mmol) in THF (10 mL) and H₂O(5 mL) was stirred at 50° C. for 3 h. Most of the solvent was removedand the residue was diluted with H₂O (5 mL). The pH of mixture wasadjusted to 4-5 by adding HCl aqueous (1 M). The precipitate wascollected and dried to give the1-(1-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)ethyl)-1H-1,2,3-triazole-4-carboxylicacid (150 mg, 65%) as a yellow solid. ESI-MS [M+H]⁺: 298.1.

Synthesis ofN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-(1-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)ethyl)-1H-1,2,3-triazole-4-carboxamide(I-124)

A mixture of1-(1-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)ethyl)-1H-1,2,3-triazole-4-carboxylicacid (150 mg, 0.51 mmol),(7-chloroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride (132 mg,0.61 mmol), HOBT (138 mg, 1.02 mmol), EDCI (196 mg, 1.02 mmol) and DIPEA(329 mg, 2.55 mmol) in DMF (5 mL) was stirred at RT for 16 h. Water (50mL) was added and extracted with EtOAc (50 mL×3). The combined organiclayers were washed with brine and dried over Na₂SO₄, and concentrated.The residue was purified by prep-TLC (DCM:MeOH=10:1) to giveN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-(1-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)ethyl)-1H-1,2,3-triazole-4-carboxamide(10 mg, yield: 4%). ESI-MS [M+H]⁺: 461.2. Purity: 100%. ¹H NMR (400 MHz,MeOD): δ 8.35 (s, 1H), 8.30 (s, 1H), 8.18-8.15 (m, 2H), 7.76 (s, 2H),7.37 (d, J=8.0 Hz, 1H), 7.10 (d, J=8 Hz, 1H), 6.61 (d, J=8.0 Hz, 1H),6.12-6.07 (m, 1H), 4.75 (s, 2H), 2.02 (d, J=8.0 Hz, 3H), 1.96-1.90 (m,1H), 0.99-0.95 (m, 2H), 0.72-0.69 (s, 2H).

Example 125

Synthesis of Ethyl 2-amino-5-bromonicotinate

To a solution of ethyl 2-aminonicotinate (25 g, 150.44 mmol) in CH₃CN(500 mL) was added NBS (32.1 g, 180.5 mmol) in portions over 30 min at0° C. The mixture was warmed to RT and stirred for 2 h. The reactionmixture was concentrated. The residue was washed with NaHCO₃ aqueous(300 mL) and extracted with EtOAc (300 mL×3), the combined organiclayers were concentrated to give ethyl 2-amino-5-bromonicotinate (36.9g, yield: 100%) as a yellow solid, which was used in the next stepwithout further purification. ESI-MS [M+H]⁺: 245.1.

Synthesis of Ethyl 2-amino-5-cyclopropylnicotinate

The mixture of ethyl 2-amino-5-bromonicotinate (14.7 g, 60.18 mmol),cyclopropylboronic acid (7.75 g, 90.27 mmol), Pd(OAc)₂ (1.35 g, 6.018mmol), SPhos (4.94 g 12.04 mmol) and K₃P₄ (44.7 g, 210.58 mmol) in amixture of toluene (200 mL) and H₂O (40 mL) was stirred at 100° C. for16 h. The reaction mixture was filtered through celite and the filtratewas washed with EA (100 mL) and concentrated. The crude product waspurified by silica gel chromatography (EA/PE=1/5) to give ethyl2-amino-5-cyclopropylnicotinate (6.0 g, yield: 48%) as a yellow solid.ESI-MS [M+H]⁺: 207.1.

Synthesis of (2-amino-5-cyclopropylpyridin-3-yl)methanol

To a stirred suspension of LiAlH4 (2.21 g, 58.2 mmol) in THF (120 mL)was added dropwise a solution of ethyl 2-amino-5-cyclopropylnicotinate(6.0 g, 29.1 mmol) at 0° C. The mixture was stirred at 0° C. for 2 h.The reaction mixture was quenched with H₂O (2.2 mL), 15% (v/v) NaOHaqueous (2.2 mL) and H₂O (6.6 mL). The mixture was stirred for 30 min at0° C. and for 2 h at RT. Filtered and washed with EtOAc (100 mL). Thefiltrate was dried, concentrated and purified by silica gelchromatography (EtOAc) to give(2-amino-5-cyclopropylpyridin-3-yl)methanol (4.4 g, yield: 92%) as ayellow solid. ESI-MS [M+H]⁺: 165.2.

Synthesis of(2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)methanol

A mixture of (2-amino-5-cyclopropylpyridin-3-yl)methanol (2 g, 12.18mmol) and 1,3-dichloropropan-2-one (4.6 g, 36.54 mmol) in DMF (20 mL)was stirred at 85° C. for 16 h. The reaction mixture was poured into H₂O(150 mL) and adjusted to pH 8 with a NaHCO₃ aqueous solution and thenextracted with EtOAc (100 mL×3). The combined organic layers were washedwith brine, dried over Na₂SO₄, concentrated and purified by silica gelchromatography (EA/PE=1/2) to give(2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)methanol (913mg, 32%) as a yellow solid. ESI-MS [M+H]⁺: 237.1.

Synthesis of benzyl1-((6-cyclopropyl-8-(hydroxymethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate

A mixture of(2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)methanol (730mg, 3.08 mmol), benzyl 1H-pyrazole-4-carboxylate (624 mg, 3.08 mmol) andCs₂CO₃ (1.5 g, 4.62 mmol) in DMF (10 mL) was stirred at RT for 16 h. Thereaction mixture was poured into H₂O (100 mL) and extracted with EtOAc(100 mL×2). The combined organic layers were washed with brine, driedover Na₂SO₄, concentrated and purified by silica gel chromatography(EA/PE=1/1) to give benzyl1-((6-cyclopropyl-8-(hydroxymethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate(1.1 g, yield: 89%) as a yellow solid. ESI-MS [M+H]⁺: 403.2.

Synthesis of benzyl1-((8-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate

To a solution of benzyl1-((6-cyclopropyl-8-(hydroxymethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate(1.1 g, 2.73 mmol) in DCM (10 mL) was added dropwise SOCl₂ (1.63 mg,13.67 mmol) at 0° C. The mixture was stirred at for RT 1 h. The reactionmixture was concentrated. The residue was dissolved in EtOAc (100 mL)and washed with NaHCO₃ (100 mL) and brine (100 mL), dried over Na₂SO₄,concentrated and dried in vacuo to give benzyl1-((8-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate(1.15 g, yield: 100%) as a yellow solid. ESI-MS [M+H]⁺: 421.1.

Synthesis of benzyl1-((6-cyclopropyl-8-(2-ethoxy-2-oxoethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate

The mixture of benzyl1-((8-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate(1.15 g, 2.73 mmol), Pd(dppf)Cl₂ (200 mg, 0.273 mmol) and Et₃N (829 mg,8.19 mmol) in EtOH (20 mL) was stirred at reflux for 16 h under CO. Thereaction mixture was concentrated and dissolved in EtOAc (100 mL),filtered and the filtrate was washed with H₂O (50 mL) and brine (50 mL),dried over Na₂SO₄, concentrated and purified by silica gelchromatography (EA/PE=1/3) to give benzyl1-((6-cyclopropyl-8-(2-ethoxy-2-oxoethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate(800 mg, yield: 64%) as a yellow solid. ESI-MS [M+H]⁺: 459.2.

Synthesis of benzyl1-((6-cyclopropyl-8-(2-hydroxyethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate

To a solution of benzyl1-((6-cyclopropyl-8-(2-ethoxy-2-oxoethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate(500 mg, 1.09 mmol) in THF (10 mL) and MeOH (1 mL) was added LiBH₄ (119mg, 5.45 mmol) in portions at 0° C. The mixture was stirred at RT for 2h. The reaction mixture was quenched with saturated NH₄Cl aqueoussolution (10 mL) and diluted with H₂O (50 mL). the mixture was extractedwith EtOAc (50 mL×3). The combined organic layers were washed withbrine, dried over Na₂SO₄, concentrated and purified by silica gelchromatography (EtOAc) to give benzyl1-((6-cyclopropyl-8-(2-hydroxyethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate(270 mg, yield: 59%) as a yellow solid. ESI-MS [M+H]⁺: 417.2.

Synthesis of benzyl1-((6-cyclopropyl-8-(2-methoxyethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate

To a solution of benzyl1-((6-cyclopropyl-8-(2-hydroxyethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate(250 mg, 0.60 mmol) in THF (6 mL) was added NaH (48 mg, 1.2 mmol) at 0°C. After stirring for 30 min, MeI (170 mg, 1.2 mmol) in THF (1 mL) wasadded. The mixture was stirred at RT for 3.5 h. The reaction mixture wasquenched with H₂O (50 mL) and extracted with EtOAc (50 mL×2). Thecombined organic layers were washed with brine, dried over Na₂SO₄,concentrated and purified by silica gel chromatography (EA/PE=1/2) togive benzyl1-((6-cyclopropyl-8-(2-methoxyethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate(70 mg, yield: 27%) as a yellow solid. ESI-MS [M+H]⁺: 417.2.

Synthesis of1-((6-cyclopropyl-8-(2-methoxyethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylicAcid

A mixture of benzyl1-((6-cyclopropyl-8-(2-methoxyethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate(70 mg, 0.163 mmol) and Pd/C (30 mg) in MeOH (5 mL) was stirred at RTfor 2 h under H₂ (balloon). The reaction mixture was filtered and thefiltrate was concentrated to give1-((6-cyclopropyl-8-(2-methoxyethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylicacid (55 mg, yield: 100%) as a yellow solid, which was used into thenext step without further purification. ESI-MS [M+H]⁺: 341.2.

Synthesis ofN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(2-methoxyethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(I-125)

A mixture of1-((6-cyclopropyl-8-(2-methoxyethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylicacid (90 mg, 0.264 mmol), HATU (110 mg, 0.29 mmol) and DIPEA (102 mg,0.792 mmol) in DMF (4 mL) was stirred at RT for 10 min.(7-chloroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloridehydeochloride (58 mg, 0.264 mmol) was added and stirred at RT for 16 h.Water (30 mL) was added and extracted with EtOAc (50 mL×3). The combinedorganic layers were washed with brine, dried over Na₂SO₄, concentratedand purified by prep-HPLC to giveN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(2-methoxyethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(30 mg, yield: 23%) as a white solid. ESI-MS [M+H]⁺: 504.2. Purity:97.98%. ¹H NMR (400 MHz, DMSO): δ 8.58 (t, J=5.7 Hz, 1H), 8.34-8.27 (m,2H), 8.22-8.15 (m, 2H), 7.87 (s, 1H), 7.79-7.75 (m, 1H), 7.65 (s, 1H),6.86 (s, 1H), 6.64 (dd, J=7.5, 2.1 Hz, 1H), 5.39 (s, 2H), 4.55 (d, J=5.7Hz, 2H), 3.67 (t, J=6.8 Hz, 2H), 3.21 (s, 3H), 3.04 (t, J=6.8 Hz, 2H),1.88 (m, 1H), 0.90 (m, 2H), 0.67-0.62 (m, 2H).

Example 126

Synthesis of Ethyl-4-chloro-2-(ethoxymethylene)-3-oxobutanoate

A solution of ethyl 4-chloro-3-oxobutanoate (8 mL, 59 mmol),triethoxymethane (59 mL) and Ac₂O (25 mL) was stirred at 120° C. for 3h. The reaction mixture was concentrated and n-heptane was added to theresidue. Solid precipitated and was filtered to giveethyl-4-chloro-2-(ethoxymethylene)-3-oxobutanoate (6 g, yield: 46%) as ayellow solid, which was used into next step without purification. ESI-MS[M+H]⁺: 221.2.

Synthesis of Ethyl 3-(chloromethyl)-1H-pyrazole-4-carboxylate

To a solution of ethyl-4-chloro-2-(ethoxymethylene)-3-oxobutanoate (3 g,13.6 mmol) in t-BuOMe (20 mL) was added N₂H₄ (3 mL). The reactionmixture was stirred at RT for 30 min. H₂O (50 mL) was added andextracted with EtOAc (50 mL×3). The combined organic layers were washedwith brine, dried over Na₂SO₄, and concentrated to give the crudeproduct, which was purified by silica gel (PE/EA=10/1) to obtain ethyl3-(chloromethyl)-1H-pyrazole-4-carboxylate (1.7 g, yield: 66.5%) as ayellow solid. ESI-MS [M+H]⁺: 189.1.

Synthesis of Ethyl 3-(cyanomethyl)-1H-pyrazole-4-carboxylate

To a solution of NaCN (390 mg, 8.0 mmol) in a mixture of CH₃CN (20 mL)and H₂O (3 mL) was added ethyl3-(chloromethyl)-1H-pyrazole-4-carboxylate (507 mg, 2.7 mmol). Thereaction mixture was stirred at RT for 1 h. Water (50 mL) was added andextracted with EtOAc (50 mL×3). The combined organic layers were washedwith brine, dried over Na₂SO₄, and concentrated to give the crudeproduct, which was purified by C-18 reverse phase chromatography toafford ethyl 3-(cyanomethyl)-1H-pyrazole-4-carboxylate (200 mg, yield:41%) as a white solid. ESI-MS [M+H]⁺: 180.2.

Synthesis of Ethyl3-(cyanomethyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate

A mixture of 2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine (103mg, 0.5 mmol), ethyl 3-(cyanomethyl)-1H-pyrazole-4-carboxylate (90 mg,0.5 mmol) and Cs₂CO₃ (489 mg, 3 mmol) in DMF (3 mL) was stirred at RTfor 3 h. The reaction mixture was diluted with H₂O (20 mL) and extractedwith EtOAc (50 mL×2). The combined organic layers were washed withbrine, dried over Na₂SO₄, and concentrated to give the crude product,which was purified by silica gel chromatography (CH₂Cl₂:CH₃OH=10:1) togive ethyl3-(cyanomethyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate(55 mg, yield: 31%) as a brown solid. ESI-MS [M+H]⁺: 350.2.

Synthesis of Ethyl3-((2H-tetrazol-5-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate

A mixture of ethyl3-(cyanomethyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate(460 mg, 1.32 mmol), NaN₃ (428 mg, 6.58 mmol), NH₄Cl (352 mg, 6.58 mmol)in DMF (5 mL) was stirred in a sealed tube at 130° C. for 6 h. Water (50mL) was added and extracted with EtOAc (50 mL×4). The combined organiclayers were concentrated to give ethyl3-((2H-tetrazol-5-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate(121 mg, yield: 23%) as a brown solid which was used into next stepwithout purification. ESI-MS [M+H]⁺: 393.2.

Synthesis of3-((2H-tetrazol-5-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylicAcid

To a solution of ethyl3-((2H-tetrazol-5-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate(121 mg, 0.31 mmol) in a mixture of THF/EtOH/H₂O (2 mL/2 mL/1 mL) wasadded LiOH H₂O (26 mg, 0.62 mmol). The mixture was stirred at 60° C. for8 h. The pH of the mixture was adjusted to 6 by adding 2 M aqueous HClsolution, and was filtered to give3-((2H-tetrazol-5-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylicacid (96 mg, yield: 85%) as a brown solid. ESI-MS [M+H]⁺: 365.1.

Synthesis of3-((2H-tetrazol-5-yl)methyl)-N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(I-126)

A mixture of3-((2H-tetrazol-5-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylicacid (40 mg, 0.11 mmol), (7-chloroimidazo[1,5-a]pyridin-1-yl)methanaminehydrochloride (24 mg, 0.11 mmol), HOBT (28 mg, 0.22 mmol), EDCI (40 mg,0.22 mmol) and DIPEA (72 mg, 0.55 mmol) in DMF (2 mL) was stirred at RTfor 18 h. Water (15 mL) was added and extracted with EtOAc (20 mL×3).The H₂O layer was concentrated to give the crude product, which waspurified by prep-HPLC to give3-((2H-tetrazol-5-yl)methyl)-N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(9.9 mg, yield: 17%) as a white solid. ESI-MS [M+H]⁺: 528.1. Purity:98.16%. ¹H NMR (400 MHz, DMSO): δ 9.08 (s, 1H), 8.32-8.28 (m, 3H), 8.17(s, 1H), 7.76-7.75 (m, 2H), 7.39 (d, J=9.3 Hz, 1H), 6.99 (dd, J=9.4, 1.7Hz, 1H), 6.63 (dd, J=7.4, 2.0 Hz, 1H), 5.30 (s, 2H), 4.54 (d, J=5.6 Hz,2H), 4.36 (s, 2H), 1.95-1.88 (m, 1H), 0.93-0.88 (m, 2H), 0.68-0.64 (m,2H).

Example 127

Synthesis of(2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)methanol

To a solution of (2-amino-5-cyclopropylpyridin-3-yl)methanol (4.8 g, 29mmol) in DMF (30 mL) was added 1,3-dichloropropan-2-one (14.8 g, 117mmol). The mixture was stirred at 95° C. for 3 h. The reaction wasquenched with NaHCO₃ aqueous (150 mL), and extracted with EtOAc (150mL×3). The combined organic layers were washed with brine, dried overNa₂SO₄, concentrated in vacuo to give the crude, which was purified withsilica gel chromatography (EtOAc/PE=1/2) to give the(2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)methanol (3.5g, yield: 51%) as a white solid. ESI-MS [M+H]⁺: 237.1.

Synthesis of benzyl1-((6-cyclopropyl-8-(hydroxymethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate

The mixture of(2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)methanol (3.5g, 14.65 mmol), benzyl 1H-pyrazole-4-carboxylate (2.8 g, 14.7 mmol) andCs₂CO₃ (11.9 g, 36.6 mmol) in DMF (15 mL) was stirred at RT for 3 h. Thereaction was quenched with H₂O (100 mL) and extracted with EtOAc (100mL×3). The combined organic layers were washed with brine, dried overNa₂SO₄ and concentrated in vacuo to give the crude, which was purifiedwith silica gel chromatography (DCM/MeOH=10/1) to give benzyl1-((6-cyclopropyl-8-(hydroxymethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate(3.16 g, yield: 54%) as a white solid. ESI-MS [M+H]⁺: 403.1.

Synthesis of benzyl1-((6-cyclopropyl-8-formylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate

The mixture of benzyl1-((6-cyclopropyl-8-(hydroxymethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate(3.16 g, 7.9 mmol) and IBX (4.4 g, 15.7 mmol) in DMSO (15 mL) wasstirred at 40° C. for 4 h. The reaction was quenched with H₂O (60 mL)and extracted with EtOAc (100 mL×3). The combined organic layers werewashed with brine, dried over Na₂SO₄ and concentrated in vacuo to givethe crude, which was purified with silica gel chromatography(DCM/MeOH=10/1) to give1-((6-cyclopropyl-8-formylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate(1.48 g, yield: 47%) as a yellow solid. ESI-MS [M+H]⁺: 401.1.

Synthesis of benzyl(Z)-1-((6-cyclopropyl-8-(3-ethoxy-3-oxoprop-1-en-1-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate

To a solution of the benzyl1-((6-cyclopropyl-8-formylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate(1.48 g, 3.7 mmol) in THF (30 mL) was added ethyl2-(triphenyl-15-phosphanylidene)acetate (1.42 g, 41 mmol), the mixturewas stirred at RT for 6 h. The reaction was concentrated in vacuo togive the crude, which was purified with silica gel chromatography(DCM/MeOH=15/1) to give benzyl1-((6-cyclopropyl-8-(2-(ethoxycarbonyl)cyclopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate(890 mg, yield: 51%) as a white solid. ESI-MS [M+H]⁺: 471.1.

Synthesis of benzyl1-((6-cyclopropyl-8-(2-(ethoxycarbonyl)cyclopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate

To a suspension of NaH (68.4 mg, 2.85 mmol) in DMSO (10 mL) was addedtrimethylsulfoxonium iodide (967 mg, 4.39 mmol) at RT. The mixture wasstirred at RT for 10 min. Then a solution of1-((6-cyclopropyl-8-(2-(ethoxycarbonyl)cyclopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate(890 mg, 1.9 mmol) in DMSO (3 mL) was added. The mixture was stirred atRT for 6 h. H₂O (50 mL) was added and extracted with EtOAc (50 mL×3).The combined organic layers were washed with brine, dried over Na₂SO₄and concentrated in vacuo to give the crude, which was purified using asilica gel column (DCM/MeOH: 10/1) to give the benzyl1-((6-cyclopropyl-8-(2-(ethoxycarbonyl)cyclopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate(545 mg, yield: 59%) as a yellow solid. ESI-MS [M+H]⁺: 485.1.

Synthesis of1-((6-cyclopropyl-8-(2-(ethoxycarbonyl)cyclopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylicAcid

To a mixture of1-((6-cyclopropyl-8-(2-(ethoxycarbonyl)cyclopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate(545 mg, 1.13 mmol) in MeOH (10 mL) was added Pd/C (100 mg). The mixturewas stirred at RT for 3 h. The reaction was filtered and concentrated invacuo to give1-((6-cyclopropyl-8-(2-(ethoxycarbonyl)cyclopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylicacid (354 mg, yield: 80%) as a yellow solid, which was used into nextstep without purification. ESI-MS [M+H]⁺: 495.1.

Synthesis Ethyl2-(2-((4-(((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-pyrazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)cyclopropane-1-carboxylate(I-127)

A mixture of1-((6-cyclopropyl-8-(2-(ethoxycarbonyl)cyclopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylicacid (354 mg, 0.72 mmol),(7-chloroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride (188 mg,0.86 mmol), DIPEA (1 mL, 7.5 mmol) and HATU (410 mg, 1.08 mmol) in DMF(5 mL) was stirred at RT for 3 h. The reaction was diluted with H₂O (30mL) and extracted with EtOAc (50 mL×3). The combined organic layers werewashed with brine, dried over Na₂SO₄ and concentrated in vacuo to givethe crude, which was purified with prep-TLC (DCM/MeOH=10/1) to giveethyl2-(2-((4-(((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-pyrazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)cyclopropane-1-carboxylate(17.5 mg, yield: 4.4%) as a white solid. ESI-MS [M+H]⁺: 558.2. ¹H NMR(400 MHz, DMSO): δ 8.59 (t, J=5.7 Hz, 1H), 8.35-8.26 (m, 2H), 8.23-8.14(m, 2H), 7.88 (s, 1H), 7.81-7.74 (m, 1H), 7.66 (s, 1H), 6.73 (d, J=1.4Hz, 1H), 6.65 (dd, J=7.5, 2.1 Hz, 1H), 5.40 (s, 2H), 4.55 (d, J=5.7 Hz,2H), 4.09 (q, J=7.1 Hz, 2H), 2.84-2.79 (m, 1H), 2.44-2.37 (m, 1H),1.89-1.82 (m, 1H), 1.76-1.73 (m, 1H), 1.49-1.41 (m, 1H), 1.19 (t, J=7.1Hz, 3H), 0.90-0.85 (m, 2H), 0.72-0.62 (m, 2H).

Example 128

Synthesis of Ethyl2-(8-cyano-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)acetate

To a solution of 2-amino-5-cyclopropylnicotinonitrile (1.5 g, 9.4 mmol)in EtOH (30 mL) was added ethyl 4-chloro-3-oxobutanoate (4.0 g, 28.2mmol) at RT and the resulting mixture was stirred at reflux for 16 h.Water (100 mL) was added to the mixture adjusted to approximately pH 8by adding a saturated NaHCO₃ solution. Then the mixture was extractedwith EtOAc (100 mL×3). The combined organic layers were washed withbrine, dried over Na₂SO₄ and concentrated to give the crude product,which was purified by silica gel chromatography (DCM/MeOH=10/1) to giveethyl 2-(8-cyano-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)acetate (1.4 g,yield: 55%) as a yellow oil. ESI-MS [M+H]⁺: 270.1.

Synthesis of2-(8-cyano-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)acetohydrazide

A mixture of ethyl2-(8-cyano-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)acetate (1.4 g, 5.2mmol) and N₂H₄.H₂O (2 mL) in EtOH (10 mL) was stirred at RT for 12 h.The mixture was then concentrated and purified by silica gelchromatography (DCM/MeOH=10/1) to give2-(8-cyano-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)acetohydrazide (1.3g, yield: 98%) as a yellow solid, which was used in the next stepwithout purification. ESI-MS [M+H]⁺: 256.1.

Synthesis of Ethyl2-(2-(2-(8-cyano-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)acetyl)hydrazinyl)-2-oxoacetate

To a solution of2-(8-cyano-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)acetohydrazide (700mg, 2.7 mmol) and DIPEA (1.05 g, 8.1 mmol) in DCM (20 mL) was addedethyl 2-chloro-2-oxoacetate (561 mg, 4.1 mmol) slowly at 0° C. Thereaction mixture was stirred at RT for 2 h. Water (30 mL) was added andthe mixture was extracted with DCM (50 mL×3). The combined organiclayers were concentrated to give the crude product, which was purifiedby silica gel chromatography (DCM/MeOH=10/1) to give ethyl2-(2-(2-(8-cyano-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)acetyl)hydrazinyl)-2-oxoacetate(500 mg, yield: 50%) as a yellow oil. ESI-MS [M+H]⁺: 356.1.

Synthesis of Ethyl5-((8-cyano-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1,3,4-oxadiazole-2-carboxylate

To a solution of ethyl2-(2-(2-(8-cyano-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)acetyl)hydrazinyl)-2-oxoacetate(500 mg, 1.4 mmol) and Et₃N (426 mg, 4.2 mmol) in DCM (10 mL) was addeda solution of TsCl (400 mg, 2.1 mmol) in DCM (5 mL) at RT, the mixturewas stirred at this temperature for 16 h. Water (30 mL) was added andthe mixture was extracted with DCM (50 mL×3). The combined organiclayers were washed with brine, dried over Na₂SO₄ and concentrated togive the crude product which was purified by silica gel chromatography(DCM/MeOH=10/1) to give ethyl5-((8-cyano-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1,3,4-oxadiazole-2-carboxylate(200 mg, yield: 42%) as a yellow oil. ESI-MS [M+H]⁺: 338.1.

Synthesis of lithium5-((8-cyano-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1,3,4-oxadiazole-2-carboxylate

A solution of ethyl5-((8-cyano-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1,3,4-oxadiazole-2-carboxylate(200 mg, 0.59 mmol) and LiOH (43 mg, 1.8 mmol) in a mixture of THF/H₂O(4 mL/2 mL) was stirred at RT for 1 h. THF were concentrated and theremaining H₂O phase was lyophilized to give lithium5-((8-cyano-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1,3,4-oxadiazole-2-carboxylate(220 mg, crude) as a red solid, which was used directly in the next stepwithout further purification. ESI-MS [M+H]⁺: 310.1.

Synthesis ofN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-5-((8-cyano-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1,3,4-oxadiazole-2-carboxamide(I-128)

A mixture of lithium5-((8-cyano-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1,3,4-oxadiazole-2-carboxylate(100 mg, 0.31 mmol), (7-chloroimidazo[1,5-a]pyridin-1-yl)methanaminehydrochloride (82 mg, 0.38 mmol), EDCI (123 mg, 0.64 mmol), HOBT (86 mg,0.64 mmol) and DIPEA (206 mg, 1.6 mmol) in DMF (5 mL) was stirred at RTfor 48 h. The mixture was diluted with DCM/MeOH (30 mL, 10/1 (v/v)) andwashed with H₂O (20 mL). The organic layer was separated, dried overNa₂SO₄ and concentrated in vacuo to give the crude product, which waspurified by silica gel chromatography (DCM/MeOH=10/1) to giveN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-5-((8-cyano-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1,3,4-oxadiazole-2-carboxamide(25 mg, yield: 17%) as a yellow solid. ESI-MS [M+H]⁺: 473.1. Purity:96.2%. ¹H NMR (400 MHz, DMSO): δ 9.77 (t, J=5.7 Hz, 1H), 8.69 (d, J=1.4Hz, 1H), 8.48 (s, 1H), 8.37-8.26 (m, 2H), 8.00 (s, 1H), 7.83 (d, J=1.9Hz, 1H), 7.77 (d, J=1.6 Hz, 1H), 6.67 (dd, J=7.4, 2.1 Hz, 1H), 4.63 (d,J=5.8 Hz, 2H), 4.52 (s, 2H), 2.01-1.95 (m, 1H), 0.99-0.91 (m, 2H),0.80-0.72 (m, 2H).

Example 129

Synthesis of 5-cyclopropylpyrimidin-2-amine

To a solution of 5-bromopyrimidin-2-amine (1.0 g, 5.75 mmol) indioxane/H₂O (20 mL/3 mL) was added cyclopropylboronic acid (1.98 g, 23mmol), palladium diacetate (134 mg, 0.63 mmol), tricyclohexyl phosphine(322 mg, 1.15 mmol) and potassium phosphate (4.24 g, 20.12 mmol). Theresulting mixture was stirred at 90° C. for 16 h. The reaction wasdiluted with H₂O (20 mL), extracted with ethyl acetate (3×50 mL), Thecombined organic layers were washed with brine, dried over anhydroussodium sulfate and concentrated. The residue was purified by flashcolumn chromatography to give 5-cyclopropylpyrimidin-2-amine (807 mg,yield: 95%). ESI-MS [M+H]⁺: 136.2.

Synthesis of 2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyrimidine

To a solution of 5-cyclopropylpyrimidin-2-amine (600 mg, 4.44 mmol) inDMF (5 mL) was added 1,3-dichloropropan-2-one (2.73 g, 22.2 mmol). Theresulting mixture was stirred at 80° C. for 2.5 h. The reaction mixturewas diluted with H₂O (50 mL), extracted with ethyl acetate (3×30 mL),The organic layers were washed with brine, dried over anhydrous sodiumsulfate and concentrated. The residue was purified by flash columnchromatography to give2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyrimidine (80 mg, Yield:9%). ESI-MS [M+H]⁺: 208.1.

Synthesis ofN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyrimidin-2-yl)methyl)-1H-pyrazole-4-carboxamide(I-129)

To a solution of 2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyrimidine(75 mg, 0.36 mmol) in DMF (2 mL) was added cesium carbonate (234 mg,0.72 mmol),N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide(97 mg, 0.36 mmol). The resulting mixture was diluted with H₂O (50 mL),extracted with ethyl acetate (3×30 mL), The organic layer was washedwith brine, dried over anhydrous sodium sulfate and concentrated. Theresidue was purified by prep-HPLC to giveN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyrimidin-2-yl)methyl)-1H-pyrazole-4-carboxamide(15 mg, Yield: 12%) as a white solid. ESI-MS [M+H]⁺: 447.1. Purity:98.61%. ¹H NMR (400 MHz, DMSO): δ 8.69 (d, J=2.0 Hz, 1H), 8.60 (t, J=5.8Hz, 1H), 8.41 (d, J=2.3 Hz, 1H), 8.30 (d, J=7.2 Hz, 2H), 8.24 (s, 1H),7.88 (s, 1H), 7.78 (s, 1H), 7.63 (s, 1H), 6.64 (dd, J=7.4, 1.8 Hz, 1H),5.43 (s, 2H), 4.55 (d, J=5.6 Hz, 2H), 1.97 (dd, J=8.9, 4.2 Hz, 1H), 0.97(d, J=6.7 Hz, 2H), 0.74 (d, J=5.9 Hz, 2H).

Example 130

Synthesis of 5,6-dimethylpyridin-2-amine

To a solution of 5,6-dimethylpyridin-2-amine (1.0 g, 8.2 mmol) in DMF(10 mL) was added 1,3-dichloropropan-2-one (4.2 g, 32.8 mmol). Theresulting mixture was stirred at 90° C. for 2 h. The reaction mixturewas diluted with H₂O (150 mL) and extracted with ethyl acetate (3×30mL). The combined organic layers were washed with brine, dried overanhydrous sodium sulfate and concentrated. The residue was purified byflash column chromatography to give2-(chloromethyl)-5,6-dimethylimidazo[1,2-a]pyridine (1.0 g, yield: 63%).ESI-MS [M+H]⁺: 195.1.

Synthesis of Ethyl1-((5,6-dimethylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate

To a solution of 2-(chloromethyl)-5,6-dimethylimidazo[1,2-a]pyridine(150 mg, 0.77 mmol) in DMF (5 mL) was added cesium carbonate (500 mg,1.54 mmol), ethyl 1H-pyrazole-4-carboxylate (119 mg, 0.85 mmol). Theresulting mixture was stirred at 50° C. for 2 h, then diluted with H₂O(50 mL), and extracted with ethyl acetate (3×30 mL). The combinedorganic layers were washed with brine, dried over anhydrous sodiumsulfate and concentrated. The residue was purified by flash columnchromatography to give ethyl1-((5,6-dimethylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate(200 mg, yield: 87%). ESI-MS [M+H]⁺: 299.2.

Synthesis of1-((5,6-dimethylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylicacid (I-131)

To a solution of ethyl1-((5,6-dimethylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate(194 mg, 0.65 mmol) in a mixed solvent of THF/H₂O (3 mL/3 mL) was addedLithium hydroxide (78 mg, 3.3 mmol). The resulting mixture was stirredat 80° C. for 2 h. THF was evaporated and the pH of the H₂O phase wasadjusted to 5 by adding 1 M HCl solution. The resulting solidprecipitate was filtered to give1-((5,6-dimethylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylicacid (160 mg, yield: 90%) which was used in the next step withoutfurther purification. ESI-MS [M+H]⁺: 270.1.

Synthesis ofN-((7-chloroimidazo[1,2-a]pyridin-2-yl)methyl)-1-((5,6-dimethylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(I-130)

To the solution of1-((5,6-dimethylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylicacid (100 mg, 0.37 mmol) in dry DMF (5 mL) was added HATU (184 mg, 0.49mmol), DIPEA (125 mg, 0.97 mmol) and(7-chloroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride (58 mg,0.37 mmol) at RT. The reaction was stirred at RT for 2 h. Water (30 mL)was added and the mixture was extracted with ethyl acetate (20 mL×3).The combined organic layers were washed with brine, dried over anhydroussodium sulfate and concentrated. The residue was purified by prep-HPLCto giveN-((7-chloroimidazo[1,2-a]pyridin-2-yl)methyl)-1-((5,6-dimethylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(33.7 mg, yield: 21%). ESI-MS [M+H]⁺: 434.1. Purity: 99.2%. 1H NMR (400MHz, DMSO): δ 8.80 (s, 1H), 8.72 (t, J=5.5 Hz, 1H), 8.40 (d, J=7.5 Hz,1H), 8.38-8.32 (m, 2H), 7.98 (s, 1H), 7.95 (s, 1H), 7.84 (d, J=9.2 Hz,1H), 7.71 (d, J=9.2 Hz, 1H), 6.87 (d, J=7.4 Hz, 1H), 5.67 (s, 2H), 4.64(d, J=5.6 Hz, 2H), 2.67 (s, 3H), 2.42 (s, 3H).

Example 131

Synthesis of2-(azidomethyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-carbonitrile

To a mixture of2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-carbonitrile (100mg, 0.43 mmol) in dry DMF (2 mL) was added NaN₃ (39 mg, 0.65 mmol) andstirred at 25° C. for 3 h. Then H₂O (20 mL) was added and extracted withEtOAc (20 mL×3). The combined organic layers were washed with brine,dried over Na₂SO₄, filtered and concentrated to give the crude product,which was purified by Prep-TLC (EtOAc/PE=3/2) to give2-(azidomethyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-carbonitrile (70mg, yield: 68%) as a yellow solid. ESI-MS [M+H]⁺: 239.2.

Synthesis of Ethyl1-((8-cyano-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate

To a mixture of2-(azidomethyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-carbonitrile (70mg, 0.29 mmol), CuSO₄ (24 mg, 0.15 mmol), sodium ascorbate (30 mg, 0.15mmol) in t-BuOH/H₂O (3/3 mL) was added ethyl propiolate (43 mg, 0.44mmol). The mixture was stirred at 25° C. for 16 h. Then H₂O (20 mL) wasadded, extracted with EtOAc (30 mL×3). The combined organic layers wereconcentrated to give ethyl1-((8-cyano-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(95 mg, crude) as a yellow solid. ESI-MS [M+H]⁺: 337.2.

Synthesis of1-((8-cyano-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicAcid

To a mixture of ethyl1-((8-cyano-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(95 mg, crude from last step) in THF/H₂O (2/2 mL) was added NaOH (34 mg,0.85 mmol). The mixture was stirred at 25° C. for 16 h, 1 M HCl wasadded to adjust pH about 5, extracted with EtOAc/MeOH (10:1, 20 mL×3),the combined organic layers were concentrated to give1-((8-cyano-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (70 mg, crude) as a grey solid. ESI-MS [M+H]⁺: 309.2.

Synthesis ofN-((7-bromo-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((8-cyano-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(I-131)

To a mixture of1-((8-cyano-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (70 mg, crude from last step),(7-bromo-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride(55 mg, 0.23 mmol), HOBT (54 mg, 0.4 mmol), EDCI (75 mg, 0.4 mmol) inDMF (3 mL) was added DIPEA (126 mg, 0.98 mmol). The mixture was stirredat 25° C. for 16 h. Then the reaction was poured into H₂O (20 mL), theprecipitate was filtered and washed with DCM (10 mL) to giveN-((7-bromo-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((8-cyano-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(60 mg, yield: 38%) as a white solid. ESI-MS [M+H]⁺: 534.1. Purity:96.81 (214 nm), 98.17 (254 nm). ¹H NMR (400 MHz, DMSO-d₆) δ 8.73-8.69(m, 2H), 8.59-8.50 (m, 2H), 8.14 (d, J=6.8 Hz, 1H), 7.99 (s, 1H), 7.80(s, 1H), 6.82 (s, 1H), 5.81 (s, 2H), 4.70 (s, 2H), 1.99-1.98 (m, 1H),0.97-0.96 (m, 2H), 0.76-075 (m, 2H).

Example 132

Synthesis of Ethyl1-((6-cyclopropyl-8-(3-hydroxyoxetan-3-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate

A mixture of3-(2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)oxetan-3-ol(1.2 g, 4.3 mmol), ethyl 1H-pyrazole-4-carboxylate (725 mg, 5.2 mmol)and Cs₂CO₃ (2.1 g, 6.45 mmol) in DMF (30 mL) was stirred at RT for 14 h.Water (150 mL) was added to the reaction, extracted with EtOAc (100mL×3). The combined organic layers were washed with brine, dried overNa₂SO₄, concentrated in vacuo to give the crude product which waspurified with silica gel chromatography (DCM/MeOH=20/1) to give theethyl1-((6-cyclopropyl-8-(3-hydroxyoxetan-3-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate(1.1 g, yield: 67%) as a yellow solid. ESI-MS [M+H]⁺: 383.2.

Synthesis of Ethyl1-((6-cyclopropyl-8-(3-(((methylthio)carbonothioyl)oxy)oxetan-3-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate

To a solution of ethyl1-((6-cyclopropyl-8-(3-hydroxyoxetan-3-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate(600 mg, 1.57 mmol) in THF (15 mL) was added NaH (127 mg, 3.14 mmol, 60%in oil) at 0° C. slowly. The resulting mixture was stirred at 0° C. for30 min. Then CS₂ (239 mg, 3.14 mmol) was added thereto at 0° C. Afterstirring for 30 min, CH₃I (446 mg, 3.14 mmol) was added and stirred atRT for 1 h. The reaction was quenched with aqueous NH₄Cl, extracted withEtOAC (30 mL×3). The combined organic layers were washed with brine,dried over Na₂SO₄, concentrated in vacuo to give the ethyl1-((6-cyclopropyl-8-(3-(((methylthio)carbonothioyl)oxy)oxetan-3-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate(650 mg crude), which was used into next step without furtherpurification. ESI-MS [M+H]⁺: 473.1

Synthesis of Ethyl1-((8-(oxetan-3-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate

A solution of ethyl1-((6-cyclopropyl-8-(3-(((methylthio)carbonothioyl)oxy)oxetan-3-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate(650 mg crude from previous step) and Bu₃SnH (917 mg, 3.14 mmol) andAIBN (515 mg, 3.14 mmol) in toluene (20 mL) was stirred at 120° C. for12 h. The reaction was concentrated in vacuo to give the residue, whichwas diluted with H₂O (50 mL), extracted with EtOAc (50 mL×3). Thecombined organic layers were washed with brine, dried over Na₂SO₄,concentrated in vacuo to give the crude product, which was purified withsilica gel chromatography (EA/PE=2/1) to give the ethyl1-((8-(oxetan-3-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate(100 mg, yield: 17% over 2 steps) as a white solid. ESI-MS [M+H]⁺:367.2.

Synthesis of1-((8-(oxetan-3-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylicAcid

A mixture of ethyl1-((8-(oxetan-3-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate(100 mg, 0.27 mmol) and LiOH (37 mg, 1.53 mmol) in THF/H₂O (10 mL/5 mL)was stirred at 50° C. for 3 h. The reaction was concentrate in vacuo togive the1-((8-(oxetan-3-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylicacid sodium salt (150 mg crude), which was used into next step withoutfurther purification. ESI-MS [M+H]⁺: 339.1.

Synthesis ofN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(oxetan-3-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(I-132)

To a solution of1-((8-(oxetan-3-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylicacid (150 mg, crude from previous step),(7-chloroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride (87 mg,0.4 mmol), HATU (177 mg, 0.47 mmol) in DMF (10 mL) was added DIPEA (200mg, 1.55 mmol). The resulting mixture was stirred at RT for 14 h. H₂O(30 mL) was added into the reaction, extracted with EtOAC (40 mL×3). Thecombined organic layers were washed with brine, dried over Na₂SO₄,concentrated in vacuo to give the crude product which was purified withPrep-TLC (DCM/MeOH=10/1) to give theN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(oxetan-3-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(25 mg, yield: 18% over 2 steps) as a white solid. ESI-MS [M+H]⁺: 502.2.Purity: 99.2 (214 nm), 99.0 (254 nm). ¹H NMR (400 MHz, DMSO-d₆) δ 8.58(t, J=5.7 Hz, 1H), 8.33-8.27 (m, 2H), 8.23 (s, 1H), 8.17 (m, 1H), 7.88(s, 1H), 7.82-7.78 (m, 1H), 7.66 (s, 1H), 7.02 (s, 1H), 6.67-6.62 (m,1H), 5.39 (s, 2H), 4.94-4.91 (m, 2H), 4.85-4.75 (m, 2H), 4.69-4.63 (m,1H), 4.55 (d, J=5.7 Hz, 2H), 1.96-1.88 (m, 1H), 0.94-0.88 (m, 2H),0.72-0.67 (m, 2H).

Example 133

Synthesis of(2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridin-1-yl)methanol

To a solution of (2-amino-5-cyclopropylpyridin-3-yl)methanol (4.8 g, 29mmol) in DMF (30 mL) was added 1,3-dichloropropan-2-one (14.8 g, 117mmol) at RT and then heated at 95° C. The reaction was monitored by LCMSuntil the starting material consumed (˜3 h). The reaction was cooled toRT, then quenched with NaHCO₃ until pH=8 and extracted with EtOAc (30mL×3). The combined organic layers were washed with brine, dried overNa₂SO₄, concentrated in vacuo to give the crude product, which waspurified with flash silica gel column (eluent: EtOAc/PE: 1/2) to givethe (2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)methanol(3.5 g, purity: 93%, yield: 51%) as a white solid. ESI-MS [M+H]⁺: 236.1.

Synthesis of benzyl1-((6-cyclopropyl-8-(hydroxymethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate

A mixture of(2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)methanol (3.5g, 14.65 mmol), benzyl 1H-pyrazole-4-carboxylate (2.8 g, 14.65 mmol) andCs₂CO₃ (11.9 g, 36.6 mmol) in DMF (15 mL) was stirred at RT for 3 h. Thereaction was quenched with H₂O (30 mL) and extracted with EtOAc (30mL×3). The combined organic layers were washed with brine, dried overNa₂SO₄, concentrated in vacuo to give the crude product which waspurified with prep-TLC (eluent: DCM/MeOH: 10/1) to give the benzyl1-((6-cyclopropyl-8-(hydroxymethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate(3.16 g, yield: 54%) as a white solid. ESI-MS [M+H]⁺: 402.1.

Synthesis of benzyl1-((6-cyclopropyl-8-formylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate

A solution of benzyl1-((6-cyclopropyl-8-(hydroxymethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate(3.16 g, 7.9 mmol) in DMSO (15 mL) was added IBX (4.4 g, 15.7 mmol) atRT and then warmed to 40° C. and stirred for 4 h. The reaction wasquenched with H₂O (30 mL) and extracted with EtOAc (30 mL×3). Thecombined organic layers were washed with brine, dried over Na₂SO₄,concentrated in vacuo to give the crude product, which was purified withsilica gel column (eluent: DCM/MeOH: 10/1) to give the1-((6-cyclopropyl-8-formylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate(1.48 g, yield: 54%) as a yellow solid. ESI-MS [M+H]⁺: 401.1.

Synthesis of benzyl(Z)-1-((6-cyclopropyl-1-(3-ethoxy-3-oxoprop-1-en-1-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate

A solution of the benzyl1-((6-cyclopropyl-8-formylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate(1.48 g, 3.7 mmol) in THF (30 mL) was added ethyl2-(triphenyl-15-phosphanylidene)acetate (1.42 g, 41 mmol) at RT andstirred for 6 h. The reaction was concentrated in vacuo to give thecrude mixture, which was purified with flash silica gel column (eluent:DCM/MeOH: 15/1) to give the benzyl1-((6-cyclopropyl-8-(2-(ethoxycarbonyl)cyclopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate(890 mg, purity: 91.5%, yield: 51%) as a white solid. ESI-MS [M+H]⁺:470.1.

Synthesis of benzyl1-((6-cyclopropyl-8-(2-(ethoxycarbonyl)cyclopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate

A mixture of1-((6-cyclopropyl-8-(2-(ethoxycarbonyl)cyclopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate(890 mg, 1.9 mmol) and trimethyl sulfoxonium iodide (627 mg, 2.85 mmol)in THF/DMSO (30/3 mL) was added NaH (190 mg, 2.85 mmol) was stirred atRT for 6 h. The reaction was quenched with H₂O (30 mL) and extractedwith EtOAc (30 mL×3). The combined organic layers were washed withbrine, dried over Na₂SO₄, concentrated in vacuo to give the crudeproduct, which was purified with flash silica gel column (eluent:DCM/MeOH: 10/1) to give the benzyl1-((6-cyclopropyl-8-(2-(ethoxycarbonyl)cyclopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate(545 mg, yield: 59%) as a yellow solid. ESI-MS [M+H]⁺: 485.2.

Synthesis of1-((6-cyclopropyl-8-(2-(ethoxycarbonyl)cyclopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylicAcid

A solution of1-((6-cyclopropyl-8-(2-(ethoxycarbonyl)cyclopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate(545 mg, 1.13 mmol) in MeOH (10 mL) was added Pd/C (50 mg) and stirredat RT under hydrogen for 3 h. The reaction was filtered through a pad ofCelite, washed with MeOH and concentrated in vacuo to give crude1-((6-cyclopropyl-8-(2-(ethoxycarbonyl)cyclopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylicacid (354 mg, yield: 80%) as a yellow solid. ESI-MS [M+H]⁺: 394.1.

Synthesis Ethyl2-(2-((4-(((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-pyrazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)cyclopropane-1-carboxylate

A mixture of1-((6-cyclopropyl-8-(2-(ethoxycarbonyl)cyclopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylic acid (35.4 mg, 0.09 mmol) in DMF (3 mL)was added (7-chloroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride(31 mg, 0.14 mmol), DIPEA (0.1 mL, 0.75 mmol), HATU (45 mg, 0.12 mmol)and stirred at RT for 3 h. The reaction was quenched with H₂O (30 mL)and extracted with EtOAc (30 mL×3). The combined organic layers werewashed with brine, dried over Na₂SO₄, and concentrated in vacuo to givethe crude product, which was purified by prep-TLC (eluent: DCM/MeOH:10/1) to give ethyl2-(2-((4-(((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-pyrazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)cyclopropane-1-carboxylate (17.5 mg, yield: 35%) as a whitesolid. ESI-MS [M+H]⁺: 558.2. Purity: 96.0 (214 nm), 95.8 (254 nm). ¹HNMR (400 MHz, DMSO-d₆) δ 8.59 (t, J=5.7 Hz, 1H), 8.35-8.26 (m, 2H),8.23-8.14 (m, 2H), 7.88 (s, 1H), 7.81-7.74 (m, 1H), 7.66 (s, 1H), 6.73(d, J=1.4 Hz, 1H), 6.65 (dd, J=7.5, 2.1 Hz, 1H), 5.40 (s, 2H), 4.55 (d,J=5.7 Hz, 2H), 4.09 (q, J=7.1 Hz, 2H), 2.84-2.79 (m, 1H), 2.44-2.37 (m,1H), 1.89-1.82 (m, 1H), 1.76-1.73 (m, 1H), 1.49-1.41 (m, 1H), 1.19 (t,J=7.1 Hz, 3H), 0.90-0.85 (m, 2H), 0.72-0.62 (m, 2H).

Synthesis of2-(2-((4-(((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-pyrazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)cyclopropane-1-carboxylicacid (I-133)

To a mixture of ethyl2-(2-((4-(((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-pyrazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)cyclopropane-1-carboxylate(56 mg, 0.1 mmol) in EtOH/H₂O (3 mL/1 mL) was added LiOH.H₂O (24 mg,0.56 mmol). The mixture was stirred at RT for 30 min. After adjusting topH=6 with HCl(aq), the reaction mixture was extracted with EtOAc (30mL×3), the combined organic layers were concentrated and the cruderesidue was purified by Prep-HPLC to give2-(2-((4-(((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-pyrazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)cyclopropane-1-carboxylicacid (30 mg, yield: 57%) as a white solid. ESI-MS [M−H]⁻: 529.8. Purity:97.1 (214 nm), 98.0 (254 nm). ¹H NMR (400 MHz, DMSO-d₆) δ 11.95 (s, 1H),8.59 (t, J=5.5 Hz, 1H), 8.31-8.29 (m, 2H), 8.20 (s, 1H), 8.17 (s, 1H),7.88 (s, 1H), 7.78 (s, 1H), 7.65 (s, 1H), 6.70 (s, 1H), 6.65 (dd, J=7.4,1.9 Hz, 1H), 5.41 (s, 2H), 4.56 (d, J=5.6 Hz, 2H), 2.84-2.75 (m, 1H),2.26-2.16 (m, 1H), 1.90-1.82 (m, 1H), 1.76-1.68 (m, 1H), 1.49-1.35 (m,1H), 0.92-1.84 (m, 2H), 0.75-0.58 (m, 2H).

Example 134

Synthesis ofN-((7-bromo-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(I-134)

To a solution of1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (100 mg, 0.35 mmol),(7-bromo-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride(114 mg, 0.41 mmol), HOBT (67 mg, 0.49 mmol) and EDCI (94 mg, 0.49 mmol)in DMF (5 mL) was added DIPEA (226 mg, 1.75 mmol). The resulting mixturewas stirred at RT for 14 h. The reaction was poured into H₂O (40 mL),and yellow solid was precipitate out. The mixture was filtered and thecake was dried to give the crude product, which was triturated with DCM(25 mL) to give theN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(65 mg, yield: 36%) as a white solid. ESI-MS [M+H]⁺: 509.0, purity:98.79 (214 nm), 98.38 (254 nm). ¹H NMR (400 MHz, DMSO-d₆) δ 8.69 (t,J=5.2 Hz, 1H), 8.55 (s, 1H), 8.45 (s, 1H), 8.35 (s, 1H), 8.14 (d, J=7.3Hz, 1H), 7.83 (s, 1H), 7.41 (d, J=9.3 Hz, 1H), 7.01 (dd, J=9.3, 1.5 Hz,1H), 6.83-6.80 (m, 1H), 5.73 (s, 2H), 4.69 (d, J=5.4 Hz, 2H), 1.96-1.89(m, 1H), 0.94-0.89 (m, 2H), 0.69-0.65 (m, 2H).

Example 135

Synthesis of 2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine

A mixture of 5-cyclopropylpyridin-2-amine (320 mg, 2.38 mmol),1,3-dichloropropan-2-one (906 mg, 7.14 mmol) in EtOH (5 mL) was stirredat 90° C. overnight. The reaction mixture was concentrated and asaturated aqueous NaHCO₃ was added until pH to about 8, and thenextracted with EtOAc (50 mL×2). The combined organic layers wereconcentrated and purified by silica gel chromatography (EA/PE=2/1) togive 2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine (200 mg,yield: 41%) as a brown solid. ESI-MS [M+H]⁺: 207.1.

Synthesis of2-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-2H-tetrazole-5-carboxylicAcid

A mixture of 2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine (104mg, 0.5 mmol), ethyl 1H-tetrazole-5-carboxylate (71 mg, 0.5 mmol) andCs₂CO₃ (323 mg, 1 mmol) in DMF (3 mL) was stirred at 55° C. for 6 h.Then H₂O was added (10 mL), pH of the mixture was adjusted to 5 byadding HCl (2 N), then lyophilized to give2-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-2H-tetrazole-5-carboxylicacid (500 mg, crude) as a yellow solid, which was used into next stepwithout purification. ESI-MS [M+H]⁺: 285.1.

Synthesis ofN-((7-bromo-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-2-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-2H-tetrazole-5-carboxamide(I-135)

A mixture of2-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-2H-tetrazole-5-carboxylicacid (250 mg, crude from last step),(7-bromo-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride(45 mg, 0.16 mmol), HOBT (73 mg, 0.54 mmol), EDCI (103 mg, 0.54 mmol)and DIPEA (174 mg, 1.35 mmol) in DMF (2 mL) was stirred at 40° C. for 26h. Water (20 mL) was added and extracted with EtOAc (30 mL×3), thecombined organic layers were washed by H₂O (10 mL), then by brine, andthen concentrated, the crude was purified by prep-HPLC to giveN-((7-bromo-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-2-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-2H-tetrazole-5-carboxamide(3.3 mg, yield: 4.03%) as a white solid. ESI-MS [M+H]⁺: 510.0. Purity:97.65% (214 nm), 99.08% (254 nm). ¹H NMR (400 MHz, DMSO-d₆) δ 9.29 (t,J=5.4 Hz, 1H), 8.45 (d, J=2.4 Hz, 1H), 8.36 (s, 1H), 8.14 (d, J=7.3 Hz,1H), 7.94 (s, 1H), 7.39 (d, J=9.3 Hz, 1H), 7.01 (dd, J=9.4, 1.7 Hz, 1H),6.82 (t, J=8 Hz, 1H), 6.06 (s, 2H), 4.71 (d, J=5.5 Hz, 2H), 1.96-1.89(m, 1H), 0.93-0.91 (m, 2H), 0.69-0.65 (m, 2H).

Example 136

Synthesis ofN-((7-bromo-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-5-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1,3,4-oxadiazole-2-carboxamide(I-136)

A mixture of lithium5-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1,3,4-oxadiazole-2-carboxylate(100.0 mg, 0.35 mmol),(7-bromo-8-fluoroimidazo[1,5-a]pyridin-1-yl)-methanamine hydrochloride(98.6 mg, 0.35 mmol), EDCI (134.4 mg, 0.70 mmol), HOBT (94.5 mg, 0.70mmol) and DIPEA (0.18 mL, 1.05 mmol) in DMF (5 mL) was stirred at 20° C.for 48 h. The mixture was concentrated to remove DMF, diluted withDCM/MeOH (300 mL, 10/1 (v/v)) and washed with H₂O (100 mL×2). Theorganic layer was separated, dried over Na₂SO₄, and concentrated invacuo to give the crude product, which was purified by Prep-HPLC to giveN-((7-bromo-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-5-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1,3,4-oxadiazole-2-carboxamide(25.5 mg, yield: 14.3%) as a light yellow solid. ESI-MS [M+H]⁺: 509.9.Purity: 95.1 (214 nm), 96.6 (254 nm). ¹H NMR (400 MHz, DMSO-d₆) δ 9.63(t, J=5.5 Hz, 1H), 8.46 (d, J=2.4 Hz, 1H), 8.33 (s, 1H), 8.15 (d, J=7.3Hz, 1H), 7.79 (s, 1H), 7.38 (d, J=9.3 Hz, 1H), 6.98 (dd, J=9.3, 1.8 Hz,1H), 6.83 (dd, J=7.3, 6.1 Hz, 1H), 4.69 (d, J=5.5 Hz, 2H), 4.43 (s, 2H),1.98-1.85 (m, 1H), 1.00-0.84 (m, 2H), 0.74-0.61 (m, 2H).

Example 137

Synthesis ofN-((7-bromo-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-5-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1,3,4-oxadiazole-2-carboxamide(I-137)

A mixture of lithium5-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1,3,4-oxadiazole-2-carboxylate(100.0 mg, 0.35 mmol),(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride(82.3 mg, 0.35 mmol), EDCI (134.4 mg, 0.70 mmol), HOBT (94.5 mg, 0.70mmol) and DIPEA (0.18 mL, 1.05 mmol) in DMF (5 mL) was stirred at 20° C.for 48 h. The mixture was concentrated to remove DMF, diluted withDCM/MeOH (300 mL, 10/1 (v/v)) and washed with H₂O (100 mL). The organiclayer was separated, dried over Na₂SO₄, and concentrated in vacuo togive the crude product, which was purified by Prep-HPLC to giveN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-5-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1,3,4-oxadiazole-2-carboxamide(30.0 mg, yield: 18.4%) as a white solid. ESI-MS [M+H]⁺: 466.2. Purity:97.6 (214 nm), 99.1 (254 nm). ¹H NMR (400 MHz, DMSO-d₆) δ 9.63 (t, J=5.4Hz, 1H), 8.45 (d, J=2.4 Hz, 1H), 8.33 (s, 1H), 8.22 (d, J=7.4 Hz, 1H),8.15 (s, 1H), 7.80 (s, 1H), 7.38 (d, J=9.3 Hz, 1H), 6.98 (dd, J=9.3, 1.7Hz, 1H), 6.84-6.70 (m, 1H), 4.69 (d, J=5.5 Hz, 2H), 4.43 (s, 2H),1.93-1.87 (m, 1H), 1.01-0.85 (m, 2H), 0.75-0.55 (m, 2H).

Example 138

Synthesis of Ethyl 2-(6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)acetate

A mixture of 6-cyclopropylpyridazin-3-amine (1.00 g, 7.40 mmol) in EtOH(10 mL) was added ethyl 4-chloro-3-oxobutanoate (3.65 g, 22.19 mmol) atRT. Then the mixture was heated to 80° C. and stirred for 16 h. Themixture was concentrated and purified by flash silica gel chromatography(0˜10% MeOH in DCM) to give ethyl2-(6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)acetate (1.1 g, crude) asdark-red oil. ESI-MS [M+H]⁺: 246.2.

Synthesis of 2-(6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)acetohydrazide

To a solution of ethyl2-(6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)acetate (1.00 g, crude fromlast step) in EtOH (10 mL) was added hydrazine hydrate (1 mL) at RT. Themixture was heated to 80° C. and stirred for 12 h. The mixture wereconcentrated and purified by flash silica gel chromatography (0˜100%EtOAc in PE) to give2-(6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)acetohydrazide (480 mg, 29%over 2 steps) as a red solid. ESI-MS [M+H]⁺: 232.1.

Synthesis of Ethyl2-(2-(2-(6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)acetyl)hydrazinyl)-2-oxoacetate

To a solution of2-(6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)acetohydrazide (477 mg,2.06 mmol) in DCM (10 mL) was added DIPEA (533.18 mg, 4.13 mmol) andethyl 2-chloro-2-oxoacetate (422.4 mg, 3.09 mmol) at 0° C. The mixturewas stirred at 0° C. for 3 h. The mixture were concentrated and purifiedby flash silica gel chromatography (0˜10% MeOH in DCM) to give ethyl2-(2-(2-(6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)acetyl)hydrazinyl)-2-oxoacetate(450 mg, yield: 65%) as a yellow solid. ESI-MS [M+H]⁺: 332.2.

Synthesis of Ethyl5-((6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methyl)-1,3,4-oxadiazole-2-carboxylate

To a solution of ethyl2-(2-(2-(6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)acetyl)hydrazinyl)-2-oxoacetate(450 mg, 1.36 mmol) in DCM (10 mL) was added TsCl (258 mg, 1.36 mmol),Et₃N (274 mg, 2.72 mmol) at RT. The mixture was stirred for 2 h. Water(20 mL) was added and extracted with EtOAc (30 mL×3). The combinedorganic layers were concentrated and purified by flash silica gelchromatography (0˜100% EtOAc in PE) to give ethyl5-((6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methy)-1,3,4-oxadiazole-2-carboxylate(240 mg, yield: 56%) as a white solid. ESI-MS [M+H]⁺: 314.2.

Synthesis of lithium5-((6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methyl)-1,3,4-oxadiazole-2-carboxylate

To a solution of ethyl5-((6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methyl)-1,3,4-oxadiazole-2-carboxylate(40 mg, 0.128 mmol) in EtOH/THF/H₂O (1 mL/1 mL/1 mL) was added LiOH H₂O(10 mg, 0.255 mmol) at RT. The mixture was heated to 40° C. stirred for0.5 h. The mixture was freeze-dried to give lithium5-((6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methyl)-1,3,4-oxadiazole-2-carboxylate(50 mg, crude) as a pink solid. ESI-MS [M+H]⁺: 286.1.

Synthesis ofN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-5-((6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methyl)-1,3,4-oxadiazole-2-carboxamide(I-138)

To a solution of lithium5-((6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methyl)-1,3,4-oxadiazole-2-carboxylate(50 mg, crude from last step) in DMF (3 mL) was added EDCI (58 mg, 0.3mmol), HOBT (40 mg, 0.2 mmol), DIPEA (65 mg, 0.5 mmol) and(7-chloroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride (54 mg,0.25 mmol) at RT. The mixture was stirred for 16 h. The mixture wasconcentrated and purified by Prep-HPLC to giveN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-5-((6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methyl)-1,3,4-oxadiazole-2-carboxamide(3 mg, yield: 5%) as a white solid. ESI-MS [M+H]⁺: 449.0. Purity: 98.12(214 nm), 97.17 (254 nm). ¹H NMR (400 MHz, DMSO-d₆) δ 9.73 (t, J=5.8 Hz,1H), 8.31-8.33 (m, 2H), 8.14 (s, 1H), 7.91 (d, J=9.6 Hz, 1H), 7.84-7.82(m, 1H), 7.08 (d, J=9.4 Hz, 1H), 6.69-6.65 (m, 1H), 4.62 (d, J=5.9 Hz,2H), 4.47 (s, 2H), 2.13-2.23 (m, 1H), 1.09-1.03 (m, 2H), 0.99-0.93 (m,2H).

Example 139

Synthesis of 2-(azidomethyl)-6-cyclopropylimidazo[1,2-b]pyridazine

A mixture of 2-(chloromethyl)-6-cyclopropylimidazo[1,2-b]pyridazine (900mg, 4.33 mmol) in dry DMF (5 mL) was added NaN₃ (631 mg, 9.71 mmol) atRT. After the mixture was stirred for 2 h, H₂O (50 mL) was added and themixture was extracted with EtOAc (50 mL×3). The combined organic layerswere concentrated and purified by flash silica gel chromatography (0-40%EtOAc in PE) to give2-(azidomethyl)-6-cyclopropylimidazo[1,2-b]pyridazine (735 mg, yield:79.16%) as dark-red oil. ESI-MS [M+H]⁺: 215.2

Synthesis of Ethyl1-((6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate

To a solution of 2-(azidomethyl)-6-cyclopropylimidazo[1,2-b]pyridazine(730 mg, 3.4 mmol) and ethyl propiolate (501.42 mg, 5.11 mmol) int-BuOH/H₂O (5 mL/5 mL) was added CuSO₄ (543 mg, 3.4 mmol) and sodiumascorbate (675 mg, 3.41 mmol) at RT. After the mixture was stirred for 2h, it was concentrated and purified by flash silica gel chromatography(0˜10% EtOAc in PE) to give ethyl1-((6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(600 mg, yield: 56%) as a red solid. ESI-MS [M+H]⁺: 313.2.

Synthesis of1-((6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicAcid

To a solution of ethyl1-((6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(100 mg, 0.32 mmol) in THF/EtOH/H₂O (0.2 mL/0.2 mL/0.2 mL) was addedLiOH (15.33 mg, 0.64 mL). The mixture was heated to 50° C. for 2 h. pHof the mixture was adjust to 5 by adding HCl (2 M), and then the mixturewas freeze-dried to give1-((6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (110 mg, crude) as a white solid. ESI-MS [M+H]⁺: 285.1.

Synthesis ofN-((7-bromo-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(I-139)

To a solution of1-((6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (110 mg, crude from last step) in DMF (5 mL) was added EDCI (101mg, 0.53 mmol), HOBT (71 mg, 0.53 mmol), DIPEA (227 mg, 1.76 mmol) and(7-bromo-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride(99 mg, 0.35 mmol) at RT. After the mixture was stirred for 16 h, thereaction was poured into H₂O, the precipitate was filtered and washed byMeOH to giveN-((7-bromo-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(25.8 mg, yield: 15%) as a white solid. ESI-MS [M+H]⁺: 510.0. Purity:97.38 (214 nm), 93.35 (254 nm). ¹H NMR (400 MHz, DMSO-d₆) δ 8.69 (t,J=5.3 Hz, 1H), 8.56 (s, 1H), 8.45 (d, J=2.2 Hz, 1H), 8.20 (s, 1H), 8.14(d, J=7.3 Hz, 1H), 7.94 (d, J=9.5 Hz, 1H), 7.11 (d, J=9.5 Hz, 1H),6.85-6.77 (m, 1H), 5.75 (s, 2H), 4.69 (d, J=5.5 Hz, 2H), 2.23-2.13 (m,1H), 1.10-1.02 (m, 2H), 1.00-0.93 (m, 2H).

Example 140

Synthesis ofN-((7-bromo-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-5-((6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methyl)-1,3,4-oxadiazole-2-carboxamide(I-140)

To a solution of lithium5-((6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methyl)-1,3,4-oxadiazole-2-carboxylate(50 mg, crude) in DMF (3 mL) was added EDCI (58 mg, 0.3 mmol), HOBT (40mg, 0.3 mmol), DIPEA (65 mg, 0.5 mmol) and(7-bromo-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride(70 mg, 0.25 mmol) at RT. The mixture was stirred for 16 h. The mixturewas concentrated and purified by Prep-HPLC to giveN-((7-bromo-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-5-((6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methyl)-1,3,4-oxadiazole-2-carboxamide(5 mg) as a yellow solid. ESI-MS [M+H]⁺: 511.0. Purity: 95.73 (214 nm),96.89 (254 nm). ¹H NMR (400 MHz, DMSO-d₆) δ 9.63 (t, J=5.4 Hz, 1H), 8.46(d, J=2.4 Hz, 1H), 8.15 (d, J=7.4 Hz, 2H), 7.91 (d, J=9.4 Hz, 1H), 7.09(d, J=9.4 Hz, 1H), 6.83 (dd, J=7.3, 6.1 Hz, 1H), 4.69 (d, J=5.5 Hz, 2H),4.47 (s, 2H), 2.21-2.14 (m, 1H), 1.12-1.02 (m, 2H), 1.01-0.92 (m, 2H).

Example 141

Synthesis of (2-amino-5-chloropyridin-3-yl)(oxetan-3-yl)methanol

To a solution of 3-bromo-5-chloropyridin-2-amine (800 mg, 3.86 mmol) inTHF (20 mL) was added n-BuLi (6.4 mL, 15.5 mmol, 2.4 M solution inhexane) at −78° C. and stirred for 10 min. Then a solution ofoxetane-3-carbaldehyde (1.3 g, 15.4 mmol) in 5 mL THF was added. Theresulting reaction was stirred at −78° C. for 5 min. The reaction wasquenched with aqueous NH₄Cl (20 mL), extracted with EtOAc (50 mL×3). Thecombined organic layers were washed with brine, dried over Na₂SO₄,concentrated in vacuo to give the crude product, which was purified withsilica gel chromatography (DCM/MeOH=10/1) to give the(2-amino-5-chloropyridin-3-yl)(oxetan-3-yl)methanol (400 mg, yield: 48%)as a yellow solid. ESI-MS [M+H]⁺: 215.2.

Synthesis of (2-amino-5-cyclopropylpyridin-3-yl)(oxetan-3-yl)methanol

A mixture of (2-amino-5-chloropyridin-3-yl)(oxetan-3-yl)methanol (400mg, 1.87 mmol), cyclopropylboronic acid (209 mg, 2.43 mmol), Pd(OAc)₂(42 mg, 0.187 mmol), SPhos (165 mg, 0.374 mmol) and K3PO4 (1.2 g, 5.61mmol) in toluene/H₂O (25 mL/2.5 mL) was stirred at 95° C. for 14 h. Thereaction mixture was filtered, and the filtrate was concentrated invacuo to give the crude product, which was purified with silica gelchromatography (DCM/MeOH=10/1) to give the(2-amino-5-cyclopropylpyridin-3-yl)(oxetan-3-yl)methanol (250 mg, yield:60.8%) as a yellow solid. ESI-MS [M+H]⁺: 221.2.

Synthesis of(2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)(oxetan-3-yl)methanol

A mixture of (2-amino-5-cyclopropylpyridin-3-yl)(oxetan-3-yl)methanol(250 mg, 1.13 mmol) and 1,3-dichloropropan-2-one (572 mg, 4.5 mmol) inDMF (10 mL) was stirred at 95° C. for 12 h. H₂O (30 mL) was added to thereaction, extracted with EtOAc (30 mL×2). The aqueous layer wasfree-dried to give the(2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)(oxetan-3-yl)methanol(200 mg crude), which was used into next step without furtherpurification. ESI-MS [M+H]⁺: 293.2

Synthesis ofN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(hydroxy(oxetan-3-yl)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(I-141)

A mixture of(2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)(oxetan-3-yl)methanol(100 mg, crude from last step),N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide(94 mg, 0.34 mmol) and Cs₂CO₃ (332 mg, 1.02 mmol) in DMF (10 mL) wasstirred at 50° C. for 12 h. H₂O (30 mL) was added to the reaction,extracted with EtOAc (40 mL×3). The combined organic layers were washedwith brine, dried over Na₂SO₄, concentrated in vacuo to give the crudeproduct, which was purified with Prep-HPLC to give theN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(hydroxy(oxetan-3-yl)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(22 mg, yield: 12%) as a white solid. ESI-MS [M+H]⁺: 531.9. Purity: 97.2(214 nm), 95.9 (254 nm). ¹H NMR (400 MHz, DMSO-d₆) δ 8.75-8.68 (m, 1H),8.64-8.59 (m, 1H), 8.53-8.30 (m, 3H), 8.22-8.18 (m, 1H), 7.99 (s, 1H),7.79 (s, 1H), 7.63 (d, J=6.3 Hz, 1H), 6.67-6.63 (m, 1H), 5.83-5.76 (m,2H), 5.02-4.98 (m, 0.5H), 4.88-4.86 (m, 0.5H), 4.61-4.46 (m, 3H),4.13-4.07 (m, 1H), 3.91-3.82 (m, 1H), 3.76-3.69 (m, 1H), 3.64-3.58 (m,1H), 3.54-3.44 (m, 1H), 2.14-2.08 (m, 1H), 1.08-1.04 (m, 2H), 0.78-0.75(m, 2H).

Example 142

Synthesis of 5-cyclopropyl-6-fluoropyridin-2-amine

To a solution of 5-bromo-6-fluoropyridin-2-amine (40 g, 209 mmol) indioxane/H₂O (400 mL/40 mL) was added cyclopropylboronic acid (36 g, 418mmol), Pd(OAc)₂ (4.7 g, 21 mmol), PCy₃ (11.75 g, 42 mmol) and K₃PO₄ (133g, 628 mmol), then the mixture was stirred at 100° C. for 16 h. Themixture was treated with H₂O (100 mL) and extracted with EtOAc (300mL×3). The organic layers were concentrated to give the crude product,which was purified by flash silica gel chromatography (PE/EA=2/1) togive 5-cyclopropyl-6-fluoropyridin-2-amine (26 g, yield: 81%) as a whitesolid. ESI-MS [M+H]⁺: 153.1.

Synthesis of2-(chloromethyl)-6-cyclopropyl-5-fluoroimidazo[1,2-a]pyridine

To a solution of 5-cyclopropyl-6-fluoropyridin-2-amine (30 g, 197 mmol)in EtOAc (50 mL) was added 1,3-dichloropropan-2-one (32.54 g, 256 mmol),then the mixture was stirred at 60° C. for 16 h. The mixture was treatedwith NaHCO₃ (aqueous) to adjust pH to 8 and then extracted with EthylAcetate. The organic layer was concentrated to give the crude productwhich was purified by flash silica gel chromatography (PE/EA=3:1) togive 2-(chloromethyl)-6-cyclopropyl-5-fluoroimidazo[1,2-a]pyridine (12.5g, yield: 28%) as a white solid. ESI-MS [M+H]⁺: 224.9.

Synthesis ofN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-5-methoxyimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide

To a solution of2-(chloromethyl)-6-cyclopropyl-5-fluoroimidazo[1,2-a]pyridine (1.94 g,8.64 mmol) in DMF (200 mL) at RT was addedN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide(2.38 g, 8.64 mmol) and Cs₂CO₃ (8.44 g, 25.9 mmol). The reaction mixturewas stirred at RT for 16 h. The mixture was concentrated to remove DMF,diluted with MeOH (200 mL) and stirred at 60° C. for 4 h and thenremoved MeOH, diluted with EtOAc (200 mL), washed with H₂O (200 mL). Theorganic layer was separated, dried over Na₂SO₄, and concentrated invacuo to give the crude product, which was purified by silica gelchromatography (DCM/MeOH=20:1 to 10:1) to giveN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-5-methoxyimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(3.5 g, yield: 85%) as a gray solid. ESI-MS [M+H]⁺: 476.1. Purity: 97.35(214 nm), 93.50 (254 nm). ¹H NMR (400 MHz, CDCl₃) S=8.0 (s, 2H), 7.82(s, 1H), 7.78 (d, J=8.0 Hz, 1H), 7.66 (s, 1H), 7.52 (s, 1H), 7.26 (d,J=8.0 Hz, 1H), 6.84 (d, J=8.0 Hz 1H), 6.63 (t, J=4.0 Hz 1H), 6.50 (dd,J=7.2, 2.0 Hz, 1H), 5.45 (s, 2H), 4.74 (d, J=5.6, 2H), 4.08 (s, 3H),2.10-2.02 (m, 1H), 1.04-0.98 (m, 2H), 0.74-0.69 (m, 2H).

Example 143

Synthesis of 5-cyclopropyl-3-(trifluoromethyl)pyridin-2-amine

To a solution of 5-bromo-3-(trifluoromethyl)pyridin-2-amine (2 g, 7.2mmol) in dioxane/H₂O (100 mL/10 mL) was added cyclopropylboronic acid(1.425 g, 16.6 mmol), Pd(OAc)₂ (186 mg, 0.83 mmol), PCy₃ (465 mg, 1.66mmol) and K₃PO₄ (3.523 g, 16.6 mmol). The reaction mixture was stirredat 100° C. for 14 h under nitrogen. Then the mixture was concentrated invacuo. Water (100 mL) was added and the mixture was extracted with EtOAc(100 mL×3). The combined organic layers were concentrated to give thecrude product, which was purified by silica gel chromatography(PE/EtOAc=10/1) to give the5-cyclopropyl-3-(trifluoromethyl)pyridin-2-amine as a yellow solid (708mg, yield: 48%). ESI-MS [M+H]⁺: 203.1.

Synthesis of2-(chloromethyl)-6-cyclopropyl-8-(trifluoromethyl)imidazo[1,2-a]pyridine

To a solution of 5-cyclopropyl-3-(trifluoromethyl)pyridin-2-amine (634mg, 3.14 mmol) and 1,3-dichloropropan-2-one (1.194 g, 9.41 mmol) in THF(30 mL). The reaction mixture was stirred at 80° C. overnight. Then H₂O(50 mL) was added and extracted with EtOAc (50 mL×3). The combinedorganic layers were concentrated to give the crude product, which waspurified by silica gel chromatography (PE/EtOAc=10/1) to give2-(chloromethyl)-6-cyclopropyl-8-(trifluoromethyl)imidazo[1,2-a]pyridine(232 mg, yield: 27%) as a white solid. ESI-MS [M+H]⁺: 275.0.

Synthesis ofN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-5-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(I-143)

To a solution of2-(chloromethyl)-6-cyclopropyl-8-(trifluoromethyl)imidazo[1,2-a]pyridine(126 mg, 0.45 mmol),N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide(126 mg, 0.45 mmol) and K₂CO₃ (127 mg, 0.917 mmol) in DMF (10 mL). Theresulting mixture was stirred overnight at 60° C. The mixture wasconcentrated to give the crude product, which was purified by silica gelchromatography (DCM/MeOH=20/1) to giveN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(58 mg, yield: 25%) as a white solid. ESI-MS [M+H]⁺: 514.1. Purity:95.44 (214 nm), 95.85 (254 nm). ¹H NMR (400 MHz, MOD) S 8.42 (s, 1H),8.28 (s, 1H), 8.19 (s, 1H), 8.18 (d, J=0.9 Hz, 1H), 7.95 (s, 1H), 7.78(s, 1H), 7.76 (s, 1H), 7.51 (s, 1H), 6.65 (dd, J=7.5, 2.0 Hz, 1H), 5.51(s, 2H), 4.71 (s, 2H), 2.07-1.98 (m, 1H), 1.01-0.97 (m, 2H), 0.75-0.72(m, 2H).

Example 144

Synthesis of 5-cyclopropyl-6-fluoropyridin-2-amine

To a solution of 5-bromo-6-fluoropyridin-2-amine (40 g, 209 mmol) indioxane/H₂O (400 mL/40 mL) was added cyclopropylboronic acid (36 g, 418mmol), Pd(OAc)₂ (4.7 g, 21 mmol), PCy₃ (11.75 g, 42 mmol) and K₃PO₄ (133g, 628 mmol), then the mixture was stirred at 100° C. for 16 h. Themixture was treated with H₂O (100 mL) and extracted with EtOAc (300mL×3). The organic layers were concentrated to give the crude product,which was purified by flash silica gel chromatography (PE/EA=2/1) togive 5-cyclopropyl-6-fluoropyridin-2-amine (26 g, yield: 81%) as a whitesolid. ESI-MS [M+H]⁺: 153.1.

Synthesis of2-(chloromethyl)-6-cyclopropyl-5-fluoroimidazo[1,2-a]pyridine

To a solution of 5-cyclopropyl-6-fluoropyridin-2-amine (30 g, 197 mmol)in EtOAc (50 mL) was added 1,3-dichloropropan-2-one (32.54 g, 256 mmol),then the mixture was stirred at 60° C. for 16 h. The mixture was treatedwith NaHCO₃ (aqueous) to adjust pH to 8 and then extracted with EthylAcetate. The organic layer was concentrated to give the crude productwhich was purified by flash silica gel chromatography (PE/EA=3:1) togive 2-(chloromethyl)-6-cyclopropyl-5-fluoroimidazo[1,2-a]pyridine (12.5g, yield: 28%) as a white solid. ESI-MS [M+H]⁺: 224.9.

Synthesis of2-(azidomethyl)-6-cyclopropyl-5-fluoroimidazo[1,2-a]pyridine

To a solution of2-(chloromethyl)-6-cyclopropyl-5-fluoroimidazo[1,2-a]pyridine (200 mg,0.89 mmol) in DMF (3 mL) was added NaN₃ (58 mg, 0.89 mmol), then themixture was stirred at RT for 5 h. Water (30 mL) was added and extractedwith EtOAc (50 mL×3). The combined organic layers were washed withbrine, dried over Na₂SO₄, filtered and concentrated to give2-(azidomethyl)-6-cyclopropyl-5-fluoroimidazo[1,2-a]pyridine (220 mg,crude) as a white solid that was used directly in the next step. ESI-MS[M+H]⁺: 232.1.

Synthesis of Ethyl1-((6-cyclopropyl-5-fluoroimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate

To a solution of2-(azidomethyl)-6-cyclopropyl-5-fluoroimidazo[1,2-a]pyridine (220 mg,crude) in t-BuOH/H₂O (5 mL/5 mL) was added ethyl propiolate (186 mg, 1.9mmol), CuSO₄ (30 mg, 0.19 mmol) and sodium ascorbate (56 mg, 0.28 mmol),then the mixture was stirred at RT for 0.5 h. The reaction mixtureshowed product precipitated which was filtered and washed with H₂O (10mL) and methanol (10 mL) to give ethyl1-((6-cyclopropyl-5-fluoroimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(250 mg, yield: 85%) as a white solid. ESI-MS [M+H]⁺: 330.1.

Synthesis of1-((6-cyclopropyl-5-fluoroimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicAcid

To a solution of ethyl1-((6-cyclopropyl-5-fluoroimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(250 mg, 0.75 mmol) in THF/H₂O (6 mL/3 mL) was added LiOH (42.03 mg,1.76 mmol), then the mixture was stirred at RT overnight. The mixturewas treated with HCl (aq) to adjust the pH to 4, the precipitate wasfiltered and washed with H₂O (10 mL) to give1-((6-cyclopropyl-5-fluoroimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (120 mg, yield: 52%) as a white solid which was used into next stepwithout further purification. ESI-MS [M+H]⁺: 302.1.

Synthesis ofN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-5-fluoroimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(I-144)

To a solution of1-((6-cyclopropyl-5-fluoroimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (60 mg, 0.2 mmol) in DMF (2 mL) was added(7-chloroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride (87 mg,0.4 mmol), HATU (151 mg, 0.4 mmol) and DIPEA (154 mg, 1.19 mmol), thenthe mixture was stirred at RT for 0.5 h. The reaction mixture was pouredinto H₂O (15 mL), the solid formed, filtered and washed with H₂O andmethanol to giveN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-5-fluoroimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(53 mg, yield: 57%) as a white solid. ESI-MS [M+H]⁺: 465.1. Purity:98.44 (214 nm), 97.99 (254 nm). ¹H NMR (400 MHz, DMSO-d₆) δ 8.93 (t,J=4.0 Hz, 1H), 8.58 (s, 1H), 8.30 (brs, 2H), 7.98 (s, 1H), 7.84 (s, 1H),7.36 (t, J=4.0 Hz, 1H), 7.03 (t, J=4.0 Hz, 1H), 6.65 (q, J=4.0 Hz, 1H),5.77 (s, 2H), 4.62 (d, J=8.0 Hz, 2H), 2.06-2.03 (m, 1H), 0.99-0.96 (m,2H), 0.77-0.74 (m, 2H).

Example 145

Synthesis ofN-((7-bromo-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-5-fluoroimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(I-145)

To a solution of1-((6-cyclopropyl-5-fluoroimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (60 mg, 0.2 mmol) in DMF (2 mL) was added(7-bromo-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine (97 mg, 0.4mmol), HATU (151 mg, 0.4 mmol) and DIPEA (154 mg, 1.19 mmol), then themixture was stirred at RT for 0.5 h. The mixture was filtrated to giveN-((7-bromo-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-5-fluoroimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(62 mg, yield: 59%) as a white solid. ESI-MS [M+H]⁺: 527.0. Purity:99.01 (214 nm), 98.76 (254 nm). ¹H NMR (400 MHz, DMSO-d₆) δ 8.70 (t,J=4.0 Hz, 1H), 8.57 (s, 1H), 8.45 (d, J=4.0 Hz, 1H), 8.13 (d, J=4.0 Hz,1H), 8.00 (s, 1H), 7.36 (d, J=4.0 Hz, 1H), 7.03 (t, J=4.0 Hz, 1H), 6.82(t, J=8.0 Hz, 1H), 5.77 (s, 2H), 4.70 (d, J=4.0 Hz, 2H), 2.06-2.01 (m,1H), 1.00-0.96 (m, 2H), 0.77-0.74 (m, 2H).

Example 146

Synthesis ofN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methyl)-1H-pyrazole-4-carboxamide(I-146)

A solution of1-((6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methyl)-1H-pyrazole-4-carboxylicacid (105 mg, 0.37 mmol),(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride(113 mg, 0.48 mmol), EDCI (86 mg, 0.45 mmol), HOBT (60 mg, 0.45 mmol)and TEA (112 mg, 1.1 mL, 0.15 mmol) in dry DMF (5 mL) was stirred at RTovernight. Then the reaction mixture was diluted with H₂O (30 mL) andextracted with EtOAC 50 mL×3). The combined organic layers were driedover Na₂SO₄, concentrated and purified by flash column chromatography(DCM:MeOH=10:1) to give the desired compoundN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methyl)-1H-pyrazole-4-carboxamide (53.8 mg, yield:31%) as a white solid. ESI-MS [M+H]⁺: 465.1. Purity: 99.88 (214 nm),100.00 (254 nm). ¹H NMR (400 MHz, DMSO-d₆) δ 8.44 (d, J=2.2 Hz, 1H),8.41 (t, J=5.0 Hz, 1H), 8.21-8.20 (m, 2H), 8.09 (s, 1H), 7.92 (d, J=9.4Hz, 1H), 7.83 (s, 1H), 7.09 (d, J=9.5 Hz, 1H), 6.76 (t, J=6.9 Hz, 1H),5.41 (s, 2H), 4.62 (d, J=5.2 Hz, 2H), 2.19-2.15 (m, 1H), 1.08-1.04 (m,2H), 0.98-0.94 (m, 2H).

Example 147

Synthesis ofN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(I-147)

To a solution of1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylicacid (60 mg, 0.21 mmol),(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride(75 mg, 0.32 mmol) and HATU (120 mg, 0.31 mmol) in DMF (3 mL) was addedDIPEA (81 mg, 0.63 mmol). The resulting reaction was stirred at RT for12 h. H₂O (25 mL) was added to the reaction, extracted with EtOAc (30mL×3). The combined organic layers were washed with brine, dried overNa₂SO₄, concentrated in vacuo to give the crude product, which waspurified with Prep-TLC (DMC/MeOH=10/1) to give theN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(20 mg, yield: 21%) as a white solid. ESI-MS [M+H]⁺: 464.1. Purity: 99.3(214 nm), 99.2 (254 nm). ¹H NMR (400 MHz, DMSO-d₆) δ 8.49-8.38 (m, 2H),8.33 (s, 1H), 8.24-8.29 (m, 2H), 7.84 (s, 1H), 7.72 (s, 1H), 7.39 (d,J=9.3 Hz, 1H), 7.01-6.96 (m, 1H), 6.80-6.72 (m, 1H), 5.38 (s, 2H), 4.62(d, J=5.2 Hz, 2H), 1.95-1.86 (m, 1H), 0.96-0.85 (m, 2H), 0.70-0.61 (m,2H).

Example 148

Synthesis ofN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(I-148)

To a suspension of1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (37 mg, 0.13 mmol) and(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride(35 mg, 0.15 mmol) in DMF (3 mL) was added HOBT (40 mg, 0.3 mmol) andEDCI (57 mg, 0.3 mmol), followed by DIPEA (65 mg, 0.5 mmol). Theresulting mixture was stirred at RT for 12 h. The reaction mixture waspoured into H₂O (15 mL) slowly. The suspension mixture was stirred for 1h, and filtered. The filtered cake was washed with H₂O (20 mL) and MeOH(20 mL) then dried under vacuum pump to give theN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamideas pale solid (30 mg, yield: 50%). ESI-MS [M+H]⁺: 465.0. Purity: 98.4%(214 nm), 98.5% (254 nm). ¹H NMR (400 MHz, DMSO-d₆): 8.70 (t, J=5.4 Hz,1H), 8.55 (s, 1H), 8.44 (d, J=2.4 Hz, 1H), 8.35 (s, 1H), 8.21 (d, J=7.4Hz, 1H), 7.83 (s, 1H), 7.41 (d, J=9.3 Hz, 1H), 7.01 (dd, J=9.4, 1.8 Hz,1H), 6.76 (dd, J=7.3, 6.6 Hz, 1H), 5.73 (s, 2H), 4.70 (d, J=5.5 Hz, 2H),1.94-1.90 (m, 1H), 0.94-0.89 (m, 2H), 0.69-0.65 (m, 2H).

Example 149

Synthesis of2-(azidomethyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-carbonitrile

To a mixture of2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-carbonitrile (200mg, 0.86 mmol) in DMF (5 mL) was added NaN₃ (91 mg, 1.4 mmol). Themixture was stirred at 25° C. for 3 h. Then H₂O (30 mL) was added,extracted with EtOAc (30 mL×3). The combined organic layers were washedwith brine, dried over Na₂SO₄, filtered and concentrated to give thecrude product, which was purified by Prep-TLC (EA/PE=3/2) to give2-(azidomethyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-carbonitrile (140mg, yield: 68%) as a yellow solid. ESI-MS [M+H]⁺: 239.2.

Synthesis of Ethyl1-((8-cyano-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate

To a mixture of2-(azidomethyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-carbonitrile (140mg, 0.58 mmol), CuSO₄ (24 mg, 0.15 mmol), sodium ascorbate (30 mg, 0.15mmol) in t-BuOH/H₂O (3/3 mL) was added ethyl propiolate (88 mg, 0.9mmol). The mixture was stirred at 25° C. for 16 h. Water (30 mL) wasadded and extracted with EtOAc (50 mL×3). The combined organic layerswere washed with brine, dried over Na₂SO₄, filtered and concentrated togive ethyl1-((8-cyano-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(95 mg, yield: 48%) as a yellow solid. ESI-MS [M+H]⁺: 337.2.

Synthesis of1-((8-cyano-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicAcid

To a mixture of ethyl1-((8-cyano-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(95 mg, 0.28 mmol) in THF/H₂O (4/2 mL) was added NaOH (34 mg, 0.85mmol). The mixture was stirred at 25° C. for 16 h. The pH of reactionwas adjusted to 4 by 1 M HCl, then concentrated to give1-((8-cyano-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (130 mg, crude) as a grey solid. ESI-MS [M+H]⁺: 309.2.

Synthesis ofN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((8-cyano-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(I-149)

To a mixture of1-((8-cyano-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (130 mg, crude from last step),(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride(58 mg, 0.25 mmol), HOBT (44 mg, 0.32 mmol), EDCI (62 mg, 0.32 mmol) inDMF (3 mL) was added DIPEA (103 mg, 0.8 mmol). The mixture was stirredat 25° C. for 16 h. The reaction was quenched by H₂O (20 mL), extractedwith EtOAc (30 mL×3). The combined organic layers were washed withbrine, dried over Na₂SO₄, filtered and concentrated to give the crudeproduct, which was purified by Prep-HPLC to giveN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((8-cyano-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(15.6 mg, yield: 13%) as a yellow solid. ESI-MS [M+H]⁺: 489.9. Purity:98.83 (214 nm), 99.11 (254 nm). ¹H NMR (400 MHz, DMSO-d₆) δ 8.64-8.63(m, 3H), 8.45 (s, 1H), 8.21 (s, 1H), 7.99-7.98 (m, 1H), 7.80 (s, 1H),6.76 (s, 1H), 5.81 (s, 2H), 4.70 (s, 2H), 1.98-1.97 (m, 1H), 0.96-0.95(m, 2H), 0.76-0.75 (m, 2H).

Example 150

Synthesis of 2-(azidomethyl)-6-cyclopropylimidazo[1,2-b]pyridazine

A mixture of 2-(chloromethyl)-6-cyclopropylimidazo[1,2-b]pyridazine (900mg, 4.33 mmol) in dry DMF (5 mL) was added NaN₃ (631 mg, 9.71 mmol) atRT. After the mixture was stirred for 2 h. Water (30 mL) was added andthe mixture was extracted with EtOAc (50 mL×3). The combined organicswere concentrated and purified by flash silica gel chromatography (0-40%EtOAc in PE) to give2-(azidomethyl)-6-cyclopropylimidazo[1,2-b]pyridazine (735 mg, yield:79%) as dark-red oil. ESI-MS [M+H]⁺: 215.2

Synthesis of Ethyl1-((6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate

To a solution of 2-(azidomethyl)-6-cyclopropylimidazo[1,2-b]pyridazine(730 mg, 3.41 mmol) and ethyl propiolate (501 mg, 5.11 mmol) int-BuOH/H₂O (5 mL/5 mL) was added CuSO₄ (543 mg, 3.41 mmol) and sodiumascorbate (675 mg, 3.41 mmol) at RT. After the mixture was stirred for 2h. The mixture were concentrated and purified by flash silica gelchromatography (0˜10% EtOAc in PE) to give ethyl1-((6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(600 mg, yield: 56%) as a red solid. ESI-MS [M+H]⁺: 313.2.

Synthesis of1-((6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicAcid

To a solution of ethyl1-((6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(100 mg, 0.32 mmol) in THF/EtOH/H₂O (2 mL/2 mL/2 mL) was added LiOH(15.33 mg, 0.64 mL). The mixture was heated to 50° C. and refluxed for 2h. HCl (2 M) was added to adjust the pH to 4 and the mixture wasfreeze-dried to give1-((6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (120 mg, crude) as a white solid. ESI-MS [M+H]⁺: 285.1.

Synthesis ofN-((7-bromo-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(I-150)

To a solution of1-((6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (120 mg, crude from last step) in DMF (3 mL) was added EDCI (111mg, 0.58 mmol), HOBT (78 mg, 0.58 mmol), DIPEA (250.06 mg, 1.93 mmol)and (7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanaminehydrochloride (90 mg, 0.38 mmol) at RT. After the mixture was stirredfor 16 h. The mixture was poured into H₂O, precipitate was filtered andwashed with H₂O and methanol to giveN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(26.1 mg, yield: 17%) as a white solid. ESI-MS [M+H]⁺: 466.1. Purity:98.56 (214 nm), 95.15 (254 nm). ¹H NMR (400 MHz, DMSO-d₆) δ 8.70 (t,J=5.4 Hz, 1H), 8.56 (s, 1H), 8.44 (d, J=2.3 Hz, 1H), 8.23-8.17 (m, 2H),7.94 (d, J=9.5 Hz, 1H), 7.11 (d, J=9.5 Hz, 1H), 6.80-6.72 (m, 1H), 5.75(s, 2H), 4.69 (d, J=5.5 Hz, 2H), 2.22-2.14 (m, 1H), 1.10-1.03 (m, 2H),1.01-0.93 (m, 2H).

Example 151

Synthesis of 5-fluoro-2-methylpyridine 1-oxide

To a stirred solution of 5-fluoro-2-methylpyridine (5 g, 45 mmol) in DCM(100 mL) was added m-CPBA (11.6 g, 67.5 mmol) at 0° C. and the mixturewas stirred at 25° C. for 16 h. The mixture was quenched with saturatedaqueous Na₂S₂O₃, stirred vigorously for 15 min, and then poured intosaturated aqueous NaHCO₃. The layers were separated, and the aqueouslayer was extracted twice more with DCM. The combined organic layerswere dried over MgSO₄, filtered and concentrated to give5-fluoro-2-methylpyridine 1-oxide (4.7 g, 82%) as a yellow solid whichwas used into next step without further purification. ESI-MS [M+H]⁺:128.2.

Synthesis of 5-fluoro-2-methyl-4-nitropyridine 1-oxide

Concentrated H₂SO₄ (15 mL) was slowly added to 5-fluoro-2-methylpyridine1-oxide (4.7 g, 37 mmol) at 0° C. A mixture of fuming HNO₃ (10 mL) andconcentrated H₂SO₄ (15 mL) was then added dropwise to the mixture at 0°C. Then the mixture was heated to 90° C. for 16 h. The mixture wasslowly poured into 400 g of ice and then neutralized with solid NH₄HCO₃.The mixture was extracted three times with DCM, and the combined organiclayers were dried over MgSO₄, filtered and concentrated to give5-fluoro-2-methyl-4-nitropyridine 1-oxide (4.7 g, 74%) as a yellow solidwhich was used without further purification. ESI-MS [M+H]⁺: 173.1.

Synthesis of 4-bromo-5-fluoro-2-methylpyridine 1-oxide

To a solution of 5-fluoro-2-methyl-4-nitropyridine 1-oxide (4.7 g, 27.3mmol) in acetic acid (40 mL) was added acetyl bromide (15 mL) dropwiseover 5 mins. After addition, the mixture was stirred at 80° C. for 16 h.The reaction mixture was poured into ice and the solution basified to pH8 with cold 2 M sodium hydroxide. The aqueous layer was extracted withDCM (100 mL×3). The combined organic layers were washed with brine,dried over Na₂SO₄, filtered and concentrated to give4-bromo-5-fluoro-2-methylpyridine 1-oxide (5.5 g, 98%) as a yellowsolid. ESI-MS [M+H]⁺: 206.0.

Synthesis of (4-bromo-5-fluoropyridin-2-yl)methyl acetate

A mixture of 4-bromo-5-fluoro-2-methylpyridine 1-oxide (5.5 g, 26.8mmol) in acetic anhydride (30 mL) was stirred at 100° C. for 2 h, thencooled to 25° C., concentrated to give the crude product, NaHCO₃ (aq)was added to adjust pH about 9, extracted with DCM (100 mL×3). Thecombined organic layers were washed with brine, dried over Na₂SO₄,filtered and concentrated to give the crude product which was purifiedby column chromatography (PE:EA=20:1 to 10:1) to give(4-bromo-5-fluoropyridin-2-yl)methyl acetate (3.2 g, yield: 48%) as ayellow oil. ESI-MS [M+H]⁺: 248.1.

Synthesis of (4-bromo-5-fluoropyridin-2-yl)methanol

To a mixture of (4-bromo-5-fluoropyridin-2-yl)methyl acetate (2.5 g, 10mmol) in MeOH/H₂O (20/2 mL) was added K₂CO₃ (7 g, 50 mmol). The mixturewas stirred at 25° C. for 16 h. Then MeOH was remove. Water (20 mL) wasadded, extracted with EtOAc (50 mL×3). The combined organic layers werewashed with brine, dried over Na₂SO₄, filtered and concentrated to give(4-bromo-5-fluoropyridin-2-yl)methanol (2 g, yield: 96%) as a yellow oilwhich was used into next step without further purification. ESI-MS[M+H]⁺: 206.0.

Synthesis of 4-bromo-5-fluoropicolinaldehyde

To a solution of oxalyl chloride (1.86 g, 14.6 mmol) in DCM (50 mL)under nitrogen was added dropwise a solution of DMSO (1.52 g, 19.5 mmol)in DCM (20 mL) at −78° C. Stirring was continued for 10 minutes. Asolution of (4-bromo-5-fluoropyridin-2-yl)methanol (2 g, 9.76 mmol) inDCM (20 mL) was then added dropwise over 20 minutes. The reaction wasstirred for 1 h. Triethylamine (4.93 g, 48.8 mmol) was added dropwiseand the reaction was allowed to warm to RT over 1.5 h. The reaction wasthen quenched by addition of H₂O (50 mL). The organics were separatedand H₂O phase was extracted with DCM (50 mL×2). Concentrated in vacuo togive 4-bromo-5-fluoropicolinaldehyde (1.2 g, yield: 59%) as a brown oilwhich was used into next step without further purification. ESI-MS[M+H]⁺: 204.2

Synthesis of(E)-N-((4-bromo-5-fluoropyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide

To a mixture of 4-bromo-5-fluoropicolinaldehyde (1.2 g, 5.9 mmol),2-methylpropane-2-sulfinamide (857 mg, 7.08 mmol) in dry THF (20 mL) wasadded Ti(OEt)₄ (4.03 g, 17.7 mmol). The mixture was stirred at 75° C.for 16 h. Water (100 mL) was added and extracted with EtOAc (100 mL×3).The combined organic layers were washed with brine, dried over Na₂SO₄,filtered and concentrated to give(E)-N-((4-bromo-5-fluoropyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide(1.8 g, crude). ESI-MS [M+H]⁺: 307.1

Synthesis ofN-((4-bromo-5-fluoropyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide

To a mixture of(E)-N-((4-bromo-5-fluoropyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide(1.8 g, crude from last step) in dry THF (30 mL) was added NaBH₄ (897mg, 23.6 mmol). The mixture was stirred at 25° C. for 3 h. Then H₂O (20mL) was added, extracted with EtOAc (50 mL×3). The combined organiclayers were washed with brine, dried over Na₂SO₄, filtered andconcentrated to give the crude product, which was purified by Prep-TLC(DCM/MeOH=10/1) to giveN-((4-bromo-5-fluoropyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide(900 mg, yield: 50% over 2 steps) as a yellow oil. ESI-MS [M+H]⁺: 309.0.

Synthesis of (4-bromo-5-fluoropyridin-2-yl)methanamine

A mixture ofN-((4-bromo-5-fluoropyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide(900 mg, 2.92 mmol) in TFA (10 mL) was stirred at 40° C. for 16 h. Thenconcentrated to give (4-bromo-5-fluoropyridin-2-yl)methanamine (590 mg,yield: 99%) as a yellow oil which was used in the next step withoutfurther purification. ESI-MS [M+H]⁺: 205.1.

Synthesis of N-((4-bromo-5-fluoropyridin-2-yl)methyl)formamide

A mixture of (4-bromo-5-fluoropyridin-2-yl)methanamine (590 mg, 2.89mmol) in HCOOH (10 mL) was stirred at 90° C. for 3 h. Then concentratedto give the crude product, which was purified by Prep-TLC(DCM/MeOH=10/1) to giveN-((4-bromo-5-fluoropyridin-2-yl)methyl)formamide (400 mg, yield: 60%)as a yellow solid. ESI-MS [M+H]⁺: 233.1.

Synthesis of 7-bromo-6-fluoroimidazo[1,5-a]pyridine

A mixture of N-((4-bromo-5-fluoropyridin-2-yl)methyl)formamide (400 mg,1.72 mmol) in POCl₃ (10 mL) was stirred at 100° C. for 1 h. Then POCl₃was concentrated, H₂O (20 mL) was added, followed by Na₂CO₃ (aq) toadjust pH about 8, extracted with EtOAc (50 mL×3). The combined organiclayers were washed with brine, dried over Na₂SO₄, filtered andconcentrated. The crude product was purified by Prep-TLC (EA/PE=2/1) togive 7-bromo-6-fluoroimidazo[1,5-a]pyridine (300 mg, yield: 81%) as ayellow solid. ESI-MS [M+H]⁺: 215.0.

Synthesis of 7-bromo-6-fluoroimidazo[1,5-a]pyridine-1-carbaldehyde

To a mixture of 7-bromo-6-fluoroimidazo[1,5-a]pyridine (300 mg, 1.4mmol) in dry DMF (1 mL) was added POCl₃ (321 mg, 2.1 mmol). The mixturewas stirred at 100° C. for 1 h. Then cooled to 25° C. and poured intoice H₂O (10 mL), the solution was basified with NH₃.H₂O and extractedwith DCM (50 mL×3). The combined organic layers were washed with brine,dried over Na₂SO₄, filtered and concentrated to give the crude product,which was purified by Prep-TLC (DCM/MeOH=25/1) to give7-bromo-6-fluoroimidazo[1,5-a]pyridine-1-carbaldehyde (80 mg, yield:23.6%) as a yellow solid. ESI-MS [M+H]⁺: 243.0.

Synthesis ofN-((7-bromo-6-fluoroimidazo[1,5-a]pyridin-1-yl)methylene)-2-methylpropane-2-sulfinamide

To a mixture of 7-bromo-6-fluoroimidazo[1,5-a]pyridine-1-carbaldehyde(50 mg, 0.2 mmol), 2-methylpropane-2-sulfinamide (30 mg, 0.24 mmol) indry THF (3 mL) was added Ti(OEt)₄ (137 mg, 0.6 mmol). The mixture wasstirred at 80° C. for 16 h. Water (20 mL) was added and extracted withEtOAc (50 mL×3). The combined organic layers were washed with brine,dried over Na₂SO₄, filtered and concentrated to giveN-((7-bromo-6-fluoroimidazo[1,5-a]pyridin-1-yl)methylene)-2-methylpropane-2-sulfinamide,which was used in the next step without further purification. (71.4 mg,crude). ESI-MS [M+H]⁺: 346.2

Synthesis ofN-((7-bromo-6-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-2-methylpropane-2-sulfinamide

To a mixture ofN-((7-bromo-6-fluoroimidazo[1,5-a]pyridin-1-yl)methylene)-2-methylpropane-2-sulfinamide(71.4 mg, crude from last step) in dry THF (3 mL) was added NaBH₄ (30mg, 0.8 mmol). The mixture was stirred at 25° C. for 3 h. Then H₂O (10mL) was added, extracted with EtOAc (50 mL×3). The combined organiclayers were washed with brine, dried over Na₂SO₄, filtered andconcentrated to give the crude product which was purified by Prep-TLC(DCM/MeOH=10/1) to giveN-((7-bromo-6-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-2-methylpropane-2-sulfinamide(60 mg, yield: 85% over 2 steps) as a yellow oil. ESI-MS [M+H]⁺: 348.1

Synthesis of (7-bromo-6-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine

A mixture ofN-((7-bromo-6-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-2-methylpropane-2-sulfinamide(60 mg, 0.17 mmol) in TFA (2 mL) was stirred at RT for 16 h. Thenconcentrated to give(7-bromo-6-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine (39 mg, crude)as a yellow solid which was used in the next step without furtherpurification. ESI-MS [M+H]⁺: 227.0.

Synthesis ofN-((7-bromo-6-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(I-151)

To a mixture of1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylicacid (20 mg, 0.071 mmol),(7-bromo-6-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine (17.2 mg, 0.071mmol), HOBT (19 mg, 0.14 mmol), EDCI (27 mg, 0.14 mmol) in DMF (3 mL)was added DIPEA (46 mg, 0.36 mmol). The mixture was stirred at 25° C.for 3 h. Water (20 mL) was added and the mixture was extracted withEtOAc (30 mL×3). The combined organic layers was concentrated andpurified by Prep-TLC (DCM/MeOH=10/1) to giveN-((7-bromo-6-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(18.9 mg, yield: 53%) as a yellow solid. ESI-MS [M+H]⁺: 507.9. Purity:94.07 (214 nm), 96.76 (254 nm). ¹H NMR (400 MHz, DMSO-D₆) S 8.65-8.59(m, 2H), 8.33-8.29 (m, 2H), 8.20-8.16 (m, 2H), 7.85 (s, 1H), 7.72 (s,1H), 7.39 (d, J=9.3 Hz, 1H), 6.99 (dd, J=9.3, 1.4 Hz, 1H), 5.38 (s, 2H),4.55 (d, J=5.7 Hz, 2H), 1.95-1.88 (m, 1H), 0.92-0.89 (m, 2H), 0.68-0.65(m, 2H).

Example 152

Synthesis of Methyl1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,4-triazole-3-carboxylate

A mixture of 2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine (207mg, 1.0 mmol), methyl 1H-1,2,4-triazole-3-carboxylate (190 mg, 1.5 mmol)and Cs₂CO₃ (1.6 g, 5 mmol) in DMF (8 mL) was stirred at 50 for 2 h. H₂O(50 mL) was added to the reaction, then extracted with EtOAc (50 mL×2).The combined organic layers were concentrated, and purified by flashsilica gel column (CH₂Cl₂/MeOH=15/1) to give methyl1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,4-triazole-3-carboxylate(130 mg, yield: 44%) as a white solid. ESI-MS [M+H]⁺: 298.1.

Synthesis of lithium1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,4-triazole-3-carboxylate

To a solution of methyl1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,4-triazole-3-carboxylate(57 mg, 0.19 mmol) in THF/EtOH/H₂O (1 mL/1 mL/0.5 mL) was added LiOH (16mg, 0.38 mmol). The mixture was stirred at 40° C. for 1 h. Thenconcentrated and lyophilized to give lithium1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,4-triazole-3-carboxylate(75 mg, crude) as a yellow solid. ESI-MS [M+H]⁺: 284.1.

Synthesis ofN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,4-triazole-3-carboxamide(I-152)

A mixture of lithium1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,4-triazole-3-carboxylate(75 mg, crude), (7-chloroimidazo[1,5-a]pyridin-1-yl)methanaminehydrochloride (41 mg, 0.19 mmol), HOBT (52 mg, 0.38 mmol), EDCI (73 mg,0.38 mmol) and DIPEA (123 mg, 0.95 mmol) in DMF (2.5 mL) was stirred at40° C. for 26 h. Water (10 mL) was added and extracted with EtOAc (30mL×2), the combined organic layers were washed with brine, concentrated,the crude was purified by flash silica gel column (CH₂Cl₂/MeOH=5/1) togiveN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,4-triazole-3-carboxamide(27.9 mg, yield: 32%) as a yellow solid. ESI-MS [M+H]⁺: 447.1. Purity:99.48% (214 nm), 100% (254 nm). ¹H NMR (400 MHz, DMSO-d₆) δ 8.83 (t,J=5.1 Hz, 1H), 8.72 (s, 1H), 8.34-8.29 (m, 3H), 7.83-7.79 (m, 2H), 7.38(d, J=9.3 Hz, 1H), 7.00 (d, J=9.1 Hz, 1H), 6.64 (d, J=6.8 Hz, 1H), 5.54(s, 2H), 4.60 (d, J=5.6 Hz, 2H), 1.95-1.88 (m, 1H), 0.96-0.85 (m, 2H),0.70-0.61 (m, 2H).

Example 153

Synthesis of Ethyl1-((6-cyclopropyl-8-(3-hydroxyoxetan-3-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate

A mixture of3-(2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)oxetan-3-ol(500 mg, 1.8 mmol) and NaN₃ (176 mg, 2.7 mmol) in DMF (15 mL) wasstirred at RT for 3 h. H₂O (30 mL) was added to the reaction, extractedwith EtOAc (50 mL×3). The combined organic layers were washed brine,dried over Na₂SO₄, concentrate in vacuo to give the crude product, whichwas purified with silica gel chromatography (EA/PE=1/1) to give the3-(2-(azidomethyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)oxetan-3-ol(420 mg, yield: 82%) as a yellow solid. ESI-MS [M+H]⁺: 286.1

Synthesis of Ethyl1-((8-(3-hydroxyoxetan-3-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate

To a solution of3-(2-(azidomethyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)oxetan-3-ol(420 mg, 1.47 mmol) in t-BuOH/H₂O (10 mL/10 mL) was added ethylpropiolate (158 mg, 1.6 mmol), CuSO₄ (70 mg, 0.44 mmol) and sodiumascorbate (87 mg, 0.44 mmol). The resulting reaction was stirred at RTfor 3 h. The reaction was concentrated in vacuo to give the residue,which was purified with silica gel chromatography (EA/PE=1/1) to givethe ethyl1-((8-(3-hydroxyoxetan-3-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(400 mg, yield: 71%) as a yellow solid. ESI-MS [M+H]⁺: 383.2

Synthesis of1-((8-(3-hydroxyoxetan-3-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicAcid

A mixture of ethyl1-((8-(3-hydroxyoxetan-3-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(400 mg, 1.05 mmol) and LiOH (140 mg, 5.8 mmol) in THF/H₂O (15 mL/5 mL)was stirred at 50° C. for 3 h. The reaction was concentrate in vacuo togive crude product, which was purified with Prep-HPLC to give1-((8-(3-hydroxyoxetan-3-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (220 mg, yield: 58%) as a yellow solid. ESI-MS [M+H]⁺: 356.2

Synthesis ofN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(3-hydroxyoxetan-3-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(I-153)

To a solution of1-((8-(3-hydroxyoxetan-3-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (100 mg, 0.28 mmol),(7-chloroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride (87 mg,0.4 mmol), HATU (177 mg, 0.47 mmol) in DMF (5 mL) was added DIPEA (200mg, 1.55 mmol). The resulting mixture was stirred at RT for 14 h. H₂O(30 mL) was added into the reaction, extracted with EtOAC (50 mL×3). Thecombined organic layers were washed with brine, dried over Na₂SO₄,concentrated in vacuo to give the crude product, which was purified withPrep-TLC (DCM/MeOH=10/1) to give theN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(3-hydroxyoxetan-3-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(30 mg, yield: 20%) as off white solid. ESI-MS [M+H]⁺: 518.9. Purity:94.5 (214 nm), 93.5 (254 nm). ¹H NMR (400 MHz, DMSO-d₆) δ 8.92 (t, J=5.9Hz, 1H), 8.56 (s, 1H), 8.34-8.28 (m, 3H), 7.85-7.82 (m, 1H), 7.79 (s,1H), 7.07 (d, J=1.4 Hz, 1H), 6.66-6.62 (m, 1H), 6.42 (s, 1H), 5.76 (s,2H), 5.22 (d, J=6.5 Hz, 2H), 4.62 (t, J=6.8 Hz, 4H), 1.98-1.91 (m, 1H),0.95-0.90 (m, 2H), 0.70-0.66 (m, 2H).

Example 154

Synthesis ofN-((7-bromo-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-5-((8-cyano-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1,3,4-oxadiazole-2-carboxamide(I-154)

A mixture of lithium5-((8-cyano-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1,3,4-oxadiazole-2-carboxylate(100 mg, 0.32 mmol),(7-bromo-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride(106 mg, 0.38 mmol), EDCI (123 mg, 0.64 mmol), HOBT (86 mg, 0.64 mmol)and DIPEA (206 mg, 1.6 mmol) in DMF (3 mL) was stirred at RT for 48 h.The mixture was concentrated to remove DMF, diluted with DCM/MeOH (30mL, 10/1 (v/v)) and washed with H₂O (10 mL×2). The organic layer wasseparated, dried over Na₂SO₄, and concentrated in vacuo to give thecrude product, which was purified by silica gel chromatography(DCM/MeOH=10/1) to giveN-((7-bromo-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-5-((8-cyano-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1,3,4-oxadiazole-2-carboxamide(25.4 mg, yield: 15%) as a yellow solid. ESI-MS [M+H]⁺: 535.0. Purity:96.4 (214 nm), 96.4 (254 nm). ¹H NMR (400 MHz, DMSO-d₆) δ 9.64 (t, J=5.4Hz, 1H), 8.69 (s, 1H), 8.46 (d, J=2.2 Hz, 1H), 8.15 (d, J=7.3 Hz, 1H),8.00 (s, 1H), 7.77 (s, 1H), 6.89-6.78 (m, 1H), 4.69 (d, J=5.4 Hz, 2H),4.53 (s, 2H), 2.00-1.95 (m, 1H), 1.02-0.91 (m, 2H), 0.82-0.70 (m, 2H).

Example 155

Synthesis of benzyl1-((6-cyclopropyl-8-(hydroxymethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate

A mixture of(2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)methanol (550mg, 2.33 mmol), benzyl 1H-pyrazole-4-carboxylate (520 mg, 2.56 mmol) andCs₂CO₃ (1.90 g, 5.83 mmol) in DMF (10 mL) was stirred at RT for 16 h.The mixture was concentrated and purified by flash silica gelchromatography (DCM/MeOH=15/1) to give benzyl1-((6-cyclopropyl-8-(hydroxymethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate(710 mg, yield: 75%) as a white solid. ESI-MS [M+H]⁺: 403.1

Synthesis of benzyl1-((8-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate

To a solution of benzyl1-((6-cyclopropyl-8-(hydroxymethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate(200 mg, 0.50 mmol) in DCM (5 mL) was added SOCl₂ (0.5 mL) at 0° C. andthe mixture was stirred for 2 h. The mixture was concentrated to givebenzyl1-((8-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate(200 mg, crude) as a yellow solid. ESI-MS [M+H]⁺: 421.1.

Synthesis of benzyl1-((6-cyclopropyl-8-(2-ethoxy-2-oxoethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate

A mixture of benzyl1-((8-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate(200 mg, 0.48 mmol), Pd(dppf)Cl₂ (40 mg, 0.048 mmol) and TEA (1.0 mL) inEtOH (6.0 mL) was stirred at 80° C. under CO for 16 h. The mixture wasconcentrated and purified by Prep-TLC (DCM/MeOH=20/1) to give benzyl1-((6-cyclopropyl-8-(2-ethoxy-2-oxoethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate(170 mg, yield: 77%) as a light yellow oil. ESI-MS [M+H]⁺: 458.9.

Synthesis of benzyl1-((6-cyclopropyl-8-(2-hydrazinyl-2-oxoethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate

A mixture of benzyl1-((6-cyclopropyl-8-(2-ethoxy-2-oxoethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate (100 mg, 0.22 mmol) and NH₂NH₂ ⁻H₂O(0.5 mL) in EtOH (6.0 mL) was stirred at RT for 16 h. The mixture wasconcentrated to give benzyl1-((6-cyclopropyl-8-(2-hydrazinyl-2-oxoethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate(100 mg, crude) as a white solid. ESI-MS [M+H]⁺: 445.1.

Synthesis of benzyl1-((8-((1,3,4-oxadiazol-2-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate

A mixture of benzyl1-((6-cyclopropyl-8-(2-hydrazinyl-2-oxoethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate (50 mg, crude from laststep), AcOH (0.15 mL) and triethoxymethane (0.15 mL) in toluene (3.0 mL)was stirred at 110° C. for 16 h. The mixture was concentrated andpurified by Prep-TLC (DCM/MeOH=10/1) to give benzyl1-((8-((1,3,4-oxadiazol-2-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate(40 mg, yield: 80%) as a yellow oil. ESI-MS [M+H]⁺: 455.1.

Synthesis of1-((8-((1,3,4-oxadiazol-2-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylicAcid

A solution of benzyl1-((8-((1,3,4-oxadiazol-2-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate (20.0 mg, 0.044mmol) and LiOH.H₂O (9.3 mg, 0.22 mmol) in a mixed solvent ofTHF/MeOH/H₂O (1 mL/1 mL/1 mL) was stirred at RT for 3 h. The pH valuewas adjusted to 3 by 1 M HCl solution and the mixture was extracted withi-PrOH/DCM=1/3 (30 mL×3). The combined organic layers were concentratedto give1-((8-((1,3,4-oxadiazol-2-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylicacid (10.0 mg, crude) as a yellow oil. This material was used directlyin the next step without further purification. ESI-MS [M+H]⁺: 365.1.

Synthesis of1-((8-((1,3,4-oxadiazol-2-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide(I-157)

A mixture of1-((8-((1,3,4-oxadiazol-2-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylic acid (10.0 mg, crude fromlast step), (7-chloroimidazo[1,5-a]pyridin-1-yl)methanaminehydrochloride (7.5 mg, 0.034 mmol), HATU (15.4 mg, 0.041 mmol) and DIPEA(10.5 mg, 0.081 mmol) in DMF (2 mL) was stirred at 20° C. for 4 h. Themixture was concentrated and purified by Prep-HPLC to give1-((8-((1,3,4-oxadiazol-2-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide(2.5 mg, yield: 11%) as a light yellow solid. ESI-MS [M+H]⁺: 528.1.Purity: 98.5 (214 nm), 93.9 (254 nm). ¹H NMR (400 MHz, DMSO-d₆) δ 9.10(s, 1H), 8.58 (t, J=5.6 Hz, 1H), 8.30 (d, J=8.4 Hz, 3H), 8.17 (s, 1H),7.87 (s, 1H), 7.78 (s, 1H), 7.69 (s, 1H), 7.00 (s, 1H), 6.65 (dd, J=7.4,2.0 Hz, 1H), 5.38 (s, 2H), 4.55 (d, J=5.7 Hz, 2H), 4.50 (s, 2H),1.98-1.84 (m, 1H), 0.93-0.89 (m, 2H), 0.66-0.63 (m, 2H).

Example 156

Synthesis ofN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-5-((6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methyl)-1,3,4-oxadiazole-2-carboxamide(I-156)

To a solution of lithium5-((6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methyl)-1,3,4-oxadiazole-2-carboxylate(50 mg, 0.13 mmol, crude) in DMF (5 mL) was added EDCI (58 mg, 0.3mmol), HOBT (40 mg, 0.3 mmol), DIPEA (65 mg, 0.5 mmol) and(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride(59 mg, 0.25 mmol). The reaction was stirred at RT for 16 h. The mixturewas poured into H₂O, the solid formed, filtered and washed with H₂O andMeOH to giveN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-5-((6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methyl)-1,3,4-oxadiazole-2-carboxamide(15 mg, yield: 25%) as a yellow solid. ESI-MS [M+H]⁺: 467.1. Purity:96.71% (214 nm), 96.91% (254 nm). H NMR (400 MHz, DMSO-d₆) δ 9.63 (t,J=5.4 Hz, 1H), 8.45 (d, J=2.2 Hz, 1H), 8.22 (d, J=7.4 Hz, 1H), 8.14 (s,1H), 7.91 (d, J=9.4 Hz, 1H), 7.09 (d, J=9.4 Hz, 1H), 6.78 (t, J=6.9 Hz,1H), 4.70 (d, J=5.5 Hz, 2H), 4.47 (s, 2H), 2.21-2.13 (m, 1H), 1.10-1.03(m, 2H), 1.00-0.93 (m, 2H).

Example 157

Synthesis of (2-amino-5-cyclopropylpyridin-3-yl)methanol

To a mixture of ethyl 2-amino-5-cyclopropylnicotinate (7.4 g, 36 mmol)in THF (70 mL) was added LAH (2.3 g, 61 mmol) was stirred at 0° C. Themixture was stirred at 0° C. for 3 h under N₂ atmosphere. The reactionwas monitored by LCMS until the starting material consumed. The reactionwas quenched with H₂O (5 mL), NaOH (15% aq., 5 mL), H₂O (15 mL), afterthe mixture was stirred for 10 min, the mixture was filtered throughcelite and concentrated to give a residue. Which was diluted with H₂O(100 mL) and extracted with EtOAc (100 mL×5). The combined organiclayers were washed with brine, dried over Na₂SO₄, concentrated in vacuoto give the crude product, which was purified with silica gel (eluent:EtOAc/PE: 1/2 to 1/0) to give the(2-amino-5-cyclopropylpyridin-3-yl)methanol (5 g, yield: 84%) as a whitesolid. ESI-MS [M+H]⁺: 165.2.

Synthesis of(2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)methanol

To a solution of (2-amino-5-cyclopropylpyridin-3-yl)methanol (5 g, 30mmol) in DMF (30 mL) was added 1,3-dichloropropan-2-one (14.8 g, 117mmol). The mixture was stirred at 95° C. for 3 h. The reaction wasmonitored by LCMS until the starting material consumed. The reaction wasquenched with saturated aqueous NaHCO₃ until pH=8 and extracted withEtOAc (100 mL×3). The combined organic layers were washed with brine,dried over Na₂SO₄, concentrated in vacuo to give the crude product,which was purified with silica gel (eluent: DCM/MeOH: 50/1 to 10/1) togive (2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)methanol(4.7 g, yield: 66%) as a yellow solid. ESI-MS [M+H]⁺: 237.1.

Synthesis of(2-(azidomethyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)methanol

To a solution of(2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)methanol (4.7g, 20 mmol) in DMF (30 mL) was added sodium azide (1.82 g, 28 mmol). Themixture was stirred at RT for 3 h. The reaction was monitored by LCMSuntil the starting material consumed. The reaction was quenched with H₂O(100 mL) and extracted with EtOAc (100 mL×3). The combined organiclayers were washed with brine, dried over Na₂SO₄, concentrated in vacuoto give the crude product, which was purified with silica gel (eluent:DCM/MeOH: 50/1 to 10/1) to give(2-(azidomethyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)methanol (2.1g, yield: 43%) as a white solid. ESI-MS [M+H]⁺: 244.2.

Synthesis of benzyl1-((6-cyclopropyl-8-(hydroxymethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate

A mixture of(2-(azidomethyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)methanol (2.1g, 8.6 mmol) benzyl propiolate (2.1 g, 13 mmol), sodium ascorbate (1.7g, 8.6 mmol), CuSO₄ (1.4 g, 8.6 mmol) in tBuOH/H₂O (20 mL/20 mL) wasstirred at RT for 3 h. The reaction was quenched with H₂O (50 mL) andextracted with EtOAc (100 mL×3). The combined organic layers were washedwith brine, dried over Na₂SO₄, concentrated in vacuo to give the crudeproduct, which was purified with silica gel (eluent: DCM/MeOH: 50/1 to10/1) to give benzyl1-((6-cyclopropyl-8-(hydroxymethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(1.4 g, yield: 40%) as a white solid. ESI-MS [M+H]⁺: 404.2.

Synthesis of benzyl1-((8-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate

To a mixture of benzyl1-((6-cyclopropyl-8-(hydroxymethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(1.4 g, 3.5 mmol) in DCM (15 mL) was added SOCl₂ (5 mL). The mixture wasstirred at RT for 3 h. The reaction was concentrated in vacuo to givethe crude of benzyl1-((8-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(1.43 g, crude) as a yellow solid. ESI-MS [M+H]⁺: 422.1.

Synthesis of benzyl1-((6-cyclopropyl-8-(2-ethoxy-2-oxoethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate

To a mixture of benzyl1-((8-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(1.4 g, 3.4 mmol) in EtOH (15 mL) was added Pd(dppf)₂Cl₂ (38 mg, 0.34mmol) and TEA (1.7 g, 17 mmol), the mixture was stirred at 65° C. for 3h under CO atmosphere. The reaction was concentrated in vacuo to givethe crude product, which was purified with silica gel (eluent: DCM/MeOH:50/1 to 10/1) to give benzyl1-((6-cyclopropyl-8-(2-ethoxy-2-oxoethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(1.1 g, yield: 70%) as a white solid. ESI-MS [M+H]⁺: 460.1.

Synthesis of1-((6-cyclopropyl-8-(2-ethoxy-2-oxoethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicAcid

To a mixture of benzyl1-((6-cyclopropyl-8-(2-ethoxy-2-oxoethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(1.1 g, 2.4 mmol) in MeOH (20 mL) was added Pd/C (10%, 200 mg). Themixture was stirred at RT under H₂ atmosphere for 12 h. The reaction wasfiltered and washed with methanol, the filtrate was concentrated invacuo to give the1-((6-cyclopropyl-8-(2-ethoxy-2-oxoethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (600 mg, yield: 67%) as a yellow solid. ESI-MS [M+H]⁺: 370.2.

Synthesis of Ethyl2-(2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)acetate(I-157a)

To a mixture of1-((6-cyclopropyl-8-(2-ethoxy-2-oxoethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (300 mg, 0.81 mmol) in DMF (5 mL) was added(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine HCl salt (228mg, 0.97 mmol), HOBT (147 mg, 1.1 mmol), EDCI (211 mg, 1.1 mmol) andDIPEA (502 mg, 4 mmol). The mixture was stirred at RT for 3 h. Thereaction was quenched with H₂O (30 mL) and extracted with EtOAc (50mL×3). The combined organic layers were washed with brine, dried overNa₂SO₄, concentrated in vacuo to give the crude product, which waspurified with silica gel (eluent: DCM/MeOH: 50/1 to 10/1) to give theethyl2-(2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)acetate(200 mg, yield: 45%) as a white solid. ESI-MS [M+H]⁺: 551.2. Purity:96.2 (214 nm), 95.9 (254 nm). ¹H NMR (400 MHz, DMSO-d₆) δ 8.69 (t, J=5.2Hz, 1H), 8.51 (s, 1H), 8.45 (s, 1H), 8.28 (s, 1H), 8.21 (d, J=7.2 Hz,1H), 7.81 (s, 1H), 6.96 (s, 1H), 6.76 (t, J=6.7 Hz, 1H), 5.72 (s, 2H),4.70 (d, J=5.2 Hz, 2H), 4.04 (q, J=7.1 Hz, 2H), 3.87 (s, 2H), 1.97-1.87(m, 1H), 1.12 (t, J=7.1 Hz, 3H), 0.98-0.88 (m, 2H), 0.70-0.62 (m, 2H).

Synthesis of2-(2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)aceticacid (I-157b)

A mixture of ethyl2-(2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)acetate(100 mg, 0.18 mmol) and NaOH (20 mg in 1 mL H₂O) in EtOH (20 mL) wasstirred at RT for 3 h. The reaction was quenched with HCl (1N, 1 mL).The resulting mixture was concentrated to give the crude which waspurified by Prep-HPLC to give2-(2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)aceticacid (18 mg, 19% yield) as a white solid. ESI-MS [M+H]⁺: 523.0. Purity:91.0 (214 nm), 94.5 (254 nm). ¹H NMR (400 MHz, DMSO-d₆) δ 8.72 (t, J=4.8Hz, 1H), 8.53 (s, 1H), 8.45 (s, 1H), 8.31-8.17 (m, 2H), 7.78 (s, 1H),6.94 (s, 1H), 6.76 (t, J=6.9 Hz, 1H), 5.72 (s, 2H), 4.70 (d, J=5.3 Hz,2H), 3.75 (s, 2H), 1.95-1.86 (m, 1H), 0.95-0.85 (m, 2H), 0.67-0.62 (m,2H).

Example 158

Synthesis ofN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-5-((8-cyano-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1,3,4-oxadiazole-2-carboxamide

A mixture of lithium5-((8-cyano-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1,3,4-oxadiazole-2-carboxylate(100 mg, 0.32 mmol), (7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine (113 mg, 0.48 mmol), EDCI (123 mg, 0.64 mmol),HOBT (86 mg, 0.64 mmol) and DIPEA (206 mg, 1.6 mmol) in DMF (3 mL) wasstirred at RT for 48 h. The mixture was concentrated to remove DMF,diluted with DCM/MeOH (30 mL, 10/1 (v/v)) and washed with H₂O (20 mL×2).The organic layers were separated, dried over Na₂SO₄, and concentratedin vacuo to give the crude product, which was purified by silica gelchromatography (DCM/MeOH=10/1) to giveN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-5-((8-cyano-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1,3,4-oxadiazole-2-carboxamide(20 mg, yield: 13%) as a yellow solid. ESI-MS [M+H]⁺: 490.9. Purity:99.0 (214 nm), 98.6 (254 nm). ¹H NMR (400 MHz, DMSO-d₆) δ 9.65 (t, J=5.4Hz, 1H), 8.69 (d, J=1.3 Hz, 1H), 8.45 (d, J=2.4 Hz, 1H), 8.22 (d, J=7.4Hz, 1H), 8.00 (s, 1H), 7.78 (d, J=1.6 Hz, 1H), 6.83-6.73 (m, 1H), 4.70(d, J=5.5 Hz, 2H), 4.53 (s, 2H), 2.02-1.95 (m, 1H), 1.02-0.89 (m, 2H),0.78-0.74 (m, 2H).

Example 159

Synthesis of 3-(methylsulfonyl)pyridin-2-amine

To a solution of 3-bromopyridin-2-amine (2 g, 11.5 mmol) in DMSO (20 mL)was added sodium methanesulfonate (1.534 g, 15 mmol), L-Proline (266 mg,2.31 mmol), CuI (220 mg, 1.16 mmol) and NaOH (92 mg, 2.31 mmol). Thereaction mixture was degassed with nitrogen for 2 min and irradiated inmicrowave at 160° C. for 40 min, and subsequently quenched with H₂O (30mL), extracted with EtOAc (50 mL×3). The combined organic layers wereconcentrated to give the crude product, which was purified by silica gelchromatography (PE/EtOAc=2/1) to give the3-(methylsulfonyl)pyridin-2-amine as a yellow solid (843 mg, yield:42%). ESI-MS [M+H]⁺: 173.1.

Synthesis of Ethyl 5-bromo-3-(methylsulfonyl)pyridin-2-amine

To a solution 3-(methylsulfonyl)pyridin-2-amine (843 mg, 4.9 mmol) inCH₃CN (20 mL) was added NBS (915 mg, 5.14 mmol) at RT. The resultingmixture was stirred at RT for 0.5 h and subsequently concentrated togive the residue, which was diluted with H₂O (50 mL) and extracted withEtOAc (50 mL×3). The combined organic layers were washed with brine,dried over Na₂SO₄, and concentrated to give the crude product, which waspurified by silica gel chromatography (PE/EtOAc=1/1) to give5-bromo-3-(methylsulfonyl)pyridin-2-amine (1.161 g, yield: 94%) as ayellow solid. ESI-MS [M+H]⁺: 250.9

Synthesis of 5-cyclopropyl-3-(methylsulfonyl)pyridin-2-amine

To a solution of 5-bromo-3-(methylsulfonyl)pyridin-2-amine (1.16 g, 4.62mmol) in dioxane/H₂O (50 mL/50 mL) was added cyclopropylboronic acid(794 mg, 9.25 mmol), Pd(OAc)₂ (104 mg, 0.46 mmol), PCy₃ (259 mg, 0.925mmol) and K₃PO₄ (1.963 g, 9.25 mmol). The reaction mixture was stirredat 100° C. for 14 h under nitrogen. Then the mixture was concentrated invacuo. Water (100 mL) was added and the mixture was extracted with EtOAc(100 mL×3). The combined organic layers were concentrated to give thecrude product, which was purified by silica gel chromatography(PE/EtOAc=1/1) to give the5-cyclopropyl-3-(methylsulfonyl)pyridin-2-amine as a yellow solid (619mg, yield: 63%). ESI-MS [M+H]⁺: 213.1.

Synthesis of2-(chloromethyl)-6-cyclopropyl-8-(methylsulfonyl)-3,8a-dihydroimidazo[1,2-a]pyridine

To a solution of 5-cyclopropyl-3-(methylsulfonyl)pyridin-2-amine (102mg, 0.45 mmol) and 1,3-dichloropropan-2-one (183 mg, 1.44 mmol) in EtOAc(10 mL). The reaction mixture was stirred at 90° C. for 20 h. Then H₂O(30 mL) was added and extracted with EtOAc (50 mL×3). The combinedorganic layers were concentrated to give the crude product, which waspurified by silica gel chromatography (PE/EtOAc=2/1) to give2-(chloromethyl)-6-cyclopropyl-8-(methylsulfonyl)-3,8a-dihydroimidazo[1,2-a]pyridine(97 mg, yield: 75%) as a yellow solid. ESI-MS [M+H]⁺: 285.0.

Synthesis ofN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(methylsulfonyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(I-159)

To a solution of2-(chloromethyl)-6-cyclopropyl-8-(methylsulfonyl)imidazo[1,2-a]pyridine(97 mg, 0.34 mmol),N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide(94 mg, 0.68 mmol) and K₂CO₃ (94 mg, 0.68 mmol) in DMF (10 mL). Theresulting mixture was stirred for overnight at 60° C. The mixture wasconcentrated to remove solvent to give the crude product, which waspurified by prep-HPLC to giveN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(methylsulfonyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(40 mg, yield: 23%) as a light yellow solid. ESI-MS [M+H]⁺: 523.9.Purity: 96.55% (214 nm), 95.34% (254 nm). ¹H NMR (400 MHz, MeOD) δ 9.07(s, 1H), 8.54 (s, 1H), 8.36 (d, J=7.6 Hz, 1H), 8.24 (s, 1H), 7.98 (s,1H), 7.92 (s, 2H), 7.81 (s, 1H), 7.00 (d, J=2.0 Hz, 1H), 5.56 (s, 2H),4.80 (s, 2H), 3.40 (s, 3H), 2.11-2.03 (m, 1H), 1.11-1.03 (m, 2H),0.81-0.76 (m, 2H).

Example 160

Synthesis of Methyl 2-amino-2-(2-methylhydrazono)acetate

A mixture of methylhydrazine sulfate (360 mg, 2.5 mmol) and K₂CO₃ (690mg, 5.0 mmol) in ethanol (10 mL) was stirred at RT for 10 minutes, andthen ethyl 2-amino-2-thioxoacetate (333 mg, 2.5 mmol) was added at 0° C.The mixture was stirred at RT overnight and filtered. The filtrate wasconcentrated and purified by Prep-TLC (DCM/MeOH=15:1) to give methyl2-amino-2-(2-methylhydrazono)acetate (180 mg, yield: 55%) as a yellowsolid. ESI-MS [M+H]⁺: 132.2

Synthesis of Methyl2-(2-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)acetamido)-2-(2-methylhydrazono)acetate

A solution of methyl 2-amino-2-(2-methylhydrazono)acetate (52 mg, 0.4mmol), 2-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)acetic acid (86.4 mg,0.4 mmol) in 1,4-dioxane (6 mL) was stirred at RT for 10 minutes, andthen T₃P (50 wt. % in EA, 524 mg, 0.8 mmol) and DIPEA (100 mg, 0.8 mmol)were added. After the mixture was stirred at RT for 1.5 h, solvent wasconcentrated and the crude product was used into the next step withoutfurther purification. ESI-MS [M+H]⁺: 330.2.

Synthesis of Methyl5-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1-methyl-1H-1,2,4-triazole-3-carboxylate

A solution of methyl2-(2-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)acetamido)-2-(2-methylhydrazono)acetate(crude from last step) in AcOH/1,4-dioxane (1:1, 5 mL) was stirred at100° C. for 2 h. Water (20 mL) was added and the mixture was extractedwith EtOAc (50 mL*3). The combined organic layers were concentrated andpurified by Prep-TLC (DCM:MeOH=15:1) to give methyl5-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1-methyl-1H-1,2,4-triazole-3-carboxylate(60 mg, yield: 48% over 2 steps) as a white solid. ESI-MS [M+H]⁺: 312.2.

Synthesis of5-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1-methyl-1H-1,2,4-triazole-3-carboxylicAcid

To a solution of methyl5-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1-methyl-1H-1,2,4-triazole-3-carboxylate(50 mg, 0.16 mmol) in ethanol (3 mL)/THF (3 mL)/H₂O (1.5 mL) was addedLiOH.H₂O (16 mg, 0.39 mmol). The mixture was stirred at 30° C. for 2 h.The mixture was concentrated and the crude product (60 mg, crude) wasused into the next step without further purification. ESI-MS [M+H]⁺:298.2.

Synthesis ofN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-5-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1-methyl-1H-1,2,4-triazole-3-carboxamide

A mixture of5-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1-methyl-1H-1,2,4-triazole-3-carboxylicacid (60 mg, crude from last step),(7-chloroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride (41 mg,0.19 mmol), and DIPEA (101 mg, 0.785 mmol) in isopropanol (6 mL) wasstirred at RT for 10 minutes. T₃P (50 wt. % in EA, 250 mg, 0.39 mmol)was added. The mixture was stirred at RT overnight. Water (10 mL) wasadded and extracted with EtOAc (30 mL*3). The combined organic layerswere concentrated and purified by Prep-HPLC to giveN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-5-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1-methyl-1H-1,2,4-triazole-3-carboxamide(7.3 mg, yield: 10% over 2 steps) as a yellow solid. ESI-MS [M+H]⁺:461.1. Purity: 98.14 (214 nm), 98.24 (254 nm). ¹H NMR (400 MHz, DMSO-d₆)δ 8.70 (t, J=5.9 Hz, 1H), 8.28-8.25 (m, 3H), 7.81 (s, 1H), 7.64 (s, 1H),7.32 (d, J=9.3 Hz, 1H), 6.92 (d, J=9.2 Hz, 1H), 6.61 (dd, J=7.4, 1.8 Hz,1H), 4.56 (d, J=5.9 Hz, 2H), 4.25 (s, 2H), 3.86 (s, 3H), 1.91-1.85 (m,1H), 0.90-0.85 (m, 2H), 0.64-0.61 (m, 2H).

Example 161

Synthesis of 2-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)acetohydrazide

A mixture of ethyl 2-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)acetate(650 mg, 2.66 mmol) and hydrazine hydrate (2.0 mL) in ethanol (8 mL) wasstirred at 80° C. overnight. The mixture was concentrated and purifiedby silica gel chromatography (DCM/MeOH=5:1) to give2-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)acetohydrazide (240 mg,yield: 39%) as a white solid. ESI-MS [M+H]⁺: 231.1

Synthesis of Ethyl2-amino-2-(2-(2-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)acetyl)hydrazono)acetate

A solution of 2-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)acetohydrazide(115 mg, 0.5 mmol) and ethyl 2-ethoxy-2-iminoacetate (145 mg, 1.0 mmol)in ethanol (2.0 mL) was stirred at RT for 3 days. The mixture wasconcentrated to get a yellow solid (165 mg, crude) which was used intothe next step without further purification. ESI-MS [M+H]⁺: 330.1.

Synthesis of Ethyl5-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-4H-1,2,4-triazole-3-carboxylate

A solution of ethyl2-amino-2-(2-(2-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)acetyl)hydrazono)acetate(165 mg, crude from last step) in xylene (4.0 mL) was stirred at 160° C.under microwave irradiation for 3 h. The mixture was concentrated andpurified by Prep-TLC (DCM/MeOH=5:1) to give ethyl5-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-4H-1,2,4-triazole-3-carboxylate(100 mg, yield: 64% over 2 steps) as a yellow solid. ESI-MS [M+H]⁺:312.1.

Synthesis of5-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-4H-1,2,4-triazole-3-carboxylicAcid

To a solution of ethyl5-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-4H-1,2,4-triazole-3-carboxylate(50 mg, 0.16 mmol) in ethanol (3 mL)/THF (3 mL)/H₂O (0.5 mL) was addedLiOH.H₂O (13.5 mg, 0.32 mmol). After the mixture was stirred at RTovernight, solvent was concentrated and the crude (60 mg) was used intothe next step without further purification. ESI-MS [M+H]⁺: 284.2.

Synthesis ofN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-5-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-4H-1,2,4-triazole-3-carboxamide(I-161)

A solution of crude5-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-4H-1,2,4-triazole-3-carboxylicacid (60 mg, crude from last step),(7-chloroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride (35 mg,0.16 mmol), and DIPEA (83 mg, 0.64 mmol) in isopropanol (6 mL) wasstirred at RT for 10 minutes. And then T₃P (50 wt. % in EA, 204 mg, 0.32mmol) was added. The mixture was stirred at RT overnight, H₂O (15 mL)was added and extracted with DCM and MeOH (10:1, 50 mL*3). The combinedorganic layers were concentrated and purified by Prep-HPLC to giveN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-5-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-4H-1,2,4-triazole-3-carboxamide(13.1 mg, yield: 18% over 2 steps) as a white solid. ESI-MS [M+H]⁺:447.2. Purity: 95.13 (214 nm), 96.02 (254 nm). ¹H NMR (400 MHz, DMSO-d₆)δ 8.83 (s, 1H), 8.24-8.22 (m, 3H), 7.79 (s, 1H), 7.55 (s, 1H), 7.27 (d,J=9.3 Hz, 1H), 6.88 (d, J=9.3 Hz, 1H), 6.58 (dd, J=7.4, 1.8 Hz, 1H),4.54 (d, J=5.9 Hz, 2H), 4.09 (s, 2H), 1.87-1.81 (m, 1H), 0.85-0.82 (m,2H), 0.61-0.57 (m, 2H).

Example 162

Synthesis of1-((6-cyclopropyl-8-(hydroxymethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylicAcid

The mixture of benzyl1-((6-cyclopropyl-8-(hydroxymethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate(260 mg, 0.646 mmol) and Pd/C (100 mg) in MeOH (6 mL) and THF (3 mL) wasstirred at RT for 2 h under H₂ (balloon). The reaction mixture wasfiltered and the filtrate was concentrated and dried in vacuo to give1-((6-cyclopropyl-8-(hydroxymethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylicacid (180 mg, yield: 89%) as a yellow solid. ESI-MS [M+H]⁺: 313.0.

Synthesis ofN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(hydroxymethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide

The mixture of1-((6-cyclopropyl-8-(hydroxymethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylicacid (180 mg, 0.576 mmol),(5-chloro-2-(1H-tetrazol-5-yl)phenyl)methanamine (188 mg, 0.864 mmol),EDCI (133 mg, 0.691 mmol), HOBT (93 mg, 0.691 mmol) and DIPEA (223 mg,1.728 mmol) in DMF (6 mL) was stirred at 25° C. for 16 h. The reactionmixture was poured into H₂O (60 mL) and the precipitate was collected,dried in vacuo to giveN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(hydroxymethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(200 mg, yield: 73%) as a pale white solid. ESI-MS [M+H]⁺: 475.9.

Synthesis ofN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((8-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide

To a stirred solution ofN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(hydroxymethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(180 mg, 0.378 mmol) in DCM (10 mL) and THF (4 mL) was added dropwise ofSOCl₂ (450 mg, 3.78 mmol) at 0° C. The mixture was stirred at RT for 1h. The reaction mixture was concentrated. The residue was dissolved inEtOAc (30 mL) and washed with NaHCO₃ (30 mL) and brine (30 mL), driedover Na₂SO₄, concentrated and dried in vacuo to giveN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((8-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(150 mg, crude) as a yellow solid. ESI-MS [M+H]⁺: 494.0.

Synthesis of Ethyl3-(2-((4-(((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-pyrazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)-2,2-dimethylpropanoate(I-162)

To a stirred solution of ethyl isobutyrate (0.53 g, 4.5 mmol) in THF (6mL) was added LDA (2.4 mL, 2 M in THF) at −40° C. under N₂. After 1 h,the solution above was added dropwise to the suspension ofN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((8-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(150 mg, crude from last step) in THF (10 mL) at −78° C. The resultingmixture was stirred for 2 h at −78° C. The reaction mixture was quenchedwith saturated aqueous NH₄C (30 mL), then adjusted the pH to 9-10 byNaHCO₃ aqueous, extracted with EtOAc/THF (50 mL×3). The combinedorganics were washed with brine, dried over Na₂SO₄, concentrated andpurified by Prep-TLC (DCM/MeOH=8/1) to give ethyl3-(2-((4-(((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-pyrazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)-2,2-dimethylpropanoate(10 mg, yield: 5%) as a white solid. ESI-MS [M+H]⁺: 574.1. Purity: 96.55(214 nm), 95.05 (254 nm). ¹H NMR (400 MHz, DMSO-d₆) δ 8.55 (t, J=5.5 Hz,1H), 8.33-8.28 (m, 2H), 8.20 (s, 1H), 8.15 (s, 1H), 7.87 (s, 1H), 7.77(s, 1H), 7.65 (s, 1H), 6.70-6.62 (m, 2H), 5.37 (s, 2H), 4.55 (d, J=5.7Hz, 2H), 3.95 (q, J=7.1 Hz, 2H), 3.09 (s, 2H), 1.91-1.83 (m, 1H),1.24-1.07 (m, 9H), 0.93-0.86 (m, 2H), 0.62-0.57 (m, 2H).

Example 163

Synthesis of 3-bromo-5-cyclopropylpyridin-2-amine

A mixture of 5-cyclopropylpyridin-2-amine (10 g, 74.5 mmol) in MeCN (130mL) was added 1-Bromo-2, 5-pyrrolidinedione (16 g, 89.4 mmol) at RT. Themixture was stirred for 3 h. The mixture was concentrated, diluted withH₂O (200 mL) and exacted by EtOAc (200 mL×3) and H₂O (250 mL). Thecombined organic phases were concentrated to give3-bromo-5-cyclopropylpyridin-2-amine (15.0 g, crude) as a yellow solid.ESI-MS [M+H]⁺: 213.0

Synthesis of Ethyl 3-(2-amino-5-cyclopropylpyridin-3-yl)acrylate

To a solution of 3-bromo-5-cyclopropylpyridin-2-amine (7.00 g, 33 mmol)in DMF (60 mL) was added TEA (15 mL), PPh₃ (1.74 g, 16.43 mmol),Pd(OAc)₂ (0.75 g 3.3 mmol) and ethyl acrylate (6 mL, 65.7 mmol) at RT.The mixture was heated to 95° C. and stirred for 16 h. Water (70 mL) wasadded and the mixture were exacted by EtOAc (100 mL×3). The organicphases were concentrated to give ethyl3-(2-amino-5-cyclopropylpyridin-3-yl)acrylate (4 g, yield: crude) as ayellow solid. ESI-MS [M+H]⁺: 233.1.

Synthesis of Ethyl 3-(2-amino-5-cyclopropylpyridin-3-yl)propanoate

To a solution of ethyl (E)-3-(2-amino-5-cyclopropylpyridin-3-yl)acrylate(4 g, crude from last step) in EtOH (50 mL)/EtOAc( ) (10 mL) was addedPd/C (400 mg) at RT. The mixture was stirred for 16 h. The mixture werefiltered and concentrated to give ethyl3-(2-amino-5-cyclopropylpyridin-3-yl)propanoate (4 g, crude) as a yellowoil. ESI-MS [M+H]⁺: 235.1.

Synthesis of Ethyl3-(2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)propanoate

To a solution of 3-(2-amino-5-cyclopropylpyridin-3-yl)propanoate (4 g,crude) in DMF (30 mL) was added 1,3-dichloropropan-2-one (11.7 g, 92mmol) at RT. The mixture was heated to 95° C. and stirred for 16 h. H₂O(100 mL) was added to reaction, exacted by EtOAc (100 mL×3). The organicphases were concentrated and purified by flash silica gel chromatography(0˜60% EtOAc in PE) to give ethyl3-(2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)propanoate(2.2 g, yield: 22% over 3 steps) as a red oil. ESI-MS [M+H]⁺: 307.1.

Synthesis of Ethyl3-(2-(azidomethyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)propanoate

To a solution of ethyl3-(2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)propanoate(2.2 g, 7.17 mmol) in DMF (30 mL) was added NaN₃ (416 mg, 6.40 mmol) atRT. The mixture was stirred for 2 h. H₂O (100 mL) was added to reaction,exacted by EtOAc (100 mL×3). The combined organic phases were washedwith brine, dried over Na₂SO₄, concentrated to give ethyl3-(2-(azidomethyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)propanoate(1.6 g, crude) as a red oil. ESI-MS [M+H]⁺: 314.1.

Synthesis of benzyl1-((6-cyclopropyl-8-(3-ethoxy-3-oxopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate

To a solution of ethyl3-(2-(azidomethyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)propanoate(1.6 g, crude) in t-BuOH/H₂O (20 mL/20 mL) was added benzyl propiolate(0.98 g, 6.13 mmol), sodium ascorbate (0.202 g, 1.02 mmol) and CuSO₄(0.163 g, 1.02 mmol) at RT. The mixture was stirred for 2 h. H₂O (50 mL)was added to reaction, exacted by DCM (50 mL×3). The combined organicphases were washed with brine, dried over Na₂SO₄, concentrated to givethe benzyl1-((6-cyclopropyl-8-(3-ethoxy-3-oxopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(1.4 g, crude) as a red oil, which was used into next step withoutfurther purification. ESI-MS [M+H]⁺: 474.2.

Synthesis of1-((6-cyclopropyl-8-(3-ethoxy-3-oxopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicAcid

To a solution of benzyl1-((6-cyclopropyl-8-(3-ethoxy-3-oxopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(250 mg, crude) in EtOH/EtOAc (20 mL/20 mL) was added Pd/C (50 mg) at RTand stirred for 1 h. The mixture was filtered and washed with MeOH (100mL), and the filtrate was concentrated to give1-((6-cyclopropyl-8-(3-ethoxy-3-oxopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (100 mg, crude) as a white solid. ESI-MS [M+H]⁺: 384.1.

Synthesis of Ethyl3-(2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)propanoate(I-163a)

To a solution of1-((6-cyclopropyl-8-(3-ethoxy-3-oxopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (100 mg, 0.261 mmol) in DMF (3 mL) was added EDCI (75 mg, 0.391mmol), HOBT (53 mg, 0.391 mmol), DIPEA (134 mg, 1.04 mmol) and(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride(63 mg, 0.268 mmol) at RT. The mixture reaction was stirred for 16 h.H₂O (30 mL) was added to the reaction, extracted with EtOAc (50 mL×4).The combined organic layers were washed with brine, dried over Na₂SO₄,concentrated in vacuo to give the crude product, which was purified byprep-HPLC to give ethyl3-(2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)propanoate(85 mg) as a white solid. ESI-MS [M+H]⁺: 565.1. Purity: 99.39 (214 nm),99.06 (254 nm). ¹H NMR (400 MHz, DMSO-d₆) δ 8.70 (t, J=5.4 Hz, 1H), 8.54(s, 1H), 8.44 (d, J=2.4 Hz, 1H), 8.26-8.18 (m, 2H), 7.77 (s, 1H), 6.84(s, 1H), 6.80-6.72 (m, 1H), 5.73 (s, 2H), 4.69 (d, J=5.5 Hz, 2H), 4.03(q, J=7.1 Hz, 2H), 3.06 (t, J=7.6 Hz, 2H), 2.76 (t, J=7.6 Hz, 2H),1.92-1.84 (m, 1H), 1.14 (t, J=7.1 Hz, 3H), 0.94-0.85 (m, 2H), 0.68-0.62(m, 2H).

Synthesis of3-(2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)propanoicacid (I-163b)

To a solution of ethyl3-(2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)propanoate(80 mg, 0.142 mmol) in EtOH/H₂O (2 mL/2 mL) was added LiOH H₂O (12 mg,0.284 mmol) at RT. The mixture reaction was stirred for 2 h. Thereaction was concentrated to give the crude product, which was purifiedby prep-HPLC to give3-(2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)propanoicacid (15.4 mg, yield: 20%) as a white solid. ESI-MS [M+H]⁺: 537.1.Purity: 95.99 (214 nm), 96.01 (254 nm). ¹H NMR (400 MHz, DMSO-d₆) δ12.00 (s, 1H), 8.71 (s, 1H), 8.55 (s, 1H), 8.45 (s, 1H), 8.26-8.14 (m,2H), 7.78 (s, 1H), 6.84 (s, 1H), 6.76 (t, J=6.6 Hz, 1H), 5.74 (s, 2H),4.70 (d, J=4.9 Hz, 2H), 3.03 (t, J=6.9 Hz, 2H), 2.69 (t, J=7.1 Hz, 2H),1.95-1.85 (m, 1H), 0.95-0.83 (m, 2H), 0.70-0.60 (m, 2H).

Example 164

Synthesis of Ethyl1-((6-cyclopropyl-5-fluoroimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate

To a solution of2-(chloromethyl)-6-cyclopropyl-5-fluoroimidazo[1,2-a]pyridine (1 g, 4.5mmol) in MeCN (20 mL) was added ethyl 1H-pyrazole-4-carboxylate (630 mg,4.5 mmol) and K₂CO₃ (1.25 g, 9.0 mmol). The reaction mixture was stirredat 80° C. for 14 h under nitrogen. Then the mixture was concentrated invacuo. Water (40 mL) was added and the mixture was extracted with EtOAc(50 mL×3). The combined organic layers were washed with brine, driedover Na₂SO₄, concentrated to give the crude product, which was purifiedby silica gel chromatography (EtOAc=100%) to give the ethyl1-((6-cyclopropyl-5-fluoroimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylateas a yellow solid (800 mg, yield: 55%). ESI-MS [M+H]⁺: 329.1.

Synthesis of1-((6-cyclopropyl-5-fluoroimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylicAcid

To a solution ethyl1-((6-cyclopropyl-5-fluoroimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate(800 mg, 2.44 mmol) in THF/H₂O (10 mL/2 mL) was added LiOH (585 mg, 24.4mmol) at RT. The resulting mixture was stirred at RT for 16 h. Themixture was poured into H₂O (20 mL), pH was adjusted to 4 by HCl (1 M)and extracted with EtOAc (50 mL×3). The combined organic layers werewashed with brine, dried over Na₂SO₄, and concentrated to give the crudeproduct, which was purified by silica gel chromatography (DCM/MeOH=10/1)to give1-((6-cyclopropyl-5-fluoroimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylicacid as a white solid (500 mg, yield: 68%). ESI-MS [M+H]⁺: 301.1.

Synthesis ofN-((7-bromo-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-5-fluoroimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(I-164)

To a solution of1-((6-cyclopropyl-5-fluoroimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylicacid (100 mg, 0.33 mmol) in DMF (5 mL) was added HATU (152 mg, 0.4 mmol)and DIPEA (0.2 mL, 1.16 mmol). After the reaction was stirred for 30mins, (7-bromo-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanaminehydrochloride (92 mg, 0.33 mmol) was added, the reaction mixture wasstirred at RT for 12 h. The mixture was poured into 30 mL of H₂O,extracted with EtOAc (50 mL×3). The combined organic layers were washedwith brine, dried over Na₂SO₄, and concentrated to give the crudeproduct which was purified by prep-TLC (DCM/MeOH=10/1) to giveN-((7-bromo-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-5-fluoroimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamideas a yellow solid (30 mg, yield: 17.3%). ESI-MS [M+H]⁺: 526.0, Purity:96.93 (214 nm), 96.51 (254 nm). ¹H NMR (400 MHz, DMSO-d₆) δ 8.11 (d,J=2.4 Hz, 1H), 8.01 (s, 1H), 7.81 (s, 1H), 7.60 (d, J=7.2 Hz, 1H), 7.53(s, 1H), 7.34 (d, J=9.2 Hz, 1H), 6.91 (t, J=9.2 Hz, 1H), 6.65 (s, 1H),6.61 (t, J=6.4 Hz, 1H), 5.47 (s, 2H), 4.87 (d, J=5.2 Hz, 2H), 2.05-1.98(m, 1H), 1.02 (q, J=5.6 Hz, 2H), 0.73 (q, J=5.6 Hz, 2H).

Example 165

Synthesis of 5-cyclopropylpyrimidin-2-amine

To a solution of 5-bromopyrimidin-2-amine (3 g, 17.24 mmol) indioxane/H₂O (30 mL/30 mL) was added cyclopropylboronic acid (2.96 g,34.48 mmol), Pd(OAc)₂ (387 mg, 1.72 mmol), P(cy)₃ (967 mg, 3.45 mmol)and K₃PO₄ (7.32 g, 34.48 mmol). The reaction mixture was stirred at 100°C. for 14 h under nitrogen. Then the mixture was concentrated in vacuo.Water (40 mL) was added and the mixture was extracted with DCM (50mL×3). The combined organic layers were concentrated to give the crudeproduct, which was purified by silica gel chromatography (PE/EA=2/1) togive 5-cyclopropylpyrimidin-2-amine as a yellow solid (1.83 g, yield:79%). ESI-MS [M+H]⁺: 136.0.

Synthesis of 2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyrimidine

To a solution 5-cyclopropylpyrimidin-2-amine (1 g, 7.4 mmol) in DME (20mL) was added 1,3-dichloropropan-2-one (1.41 g, 11.1 mmol), then themixture was stirred at 95° C. for 12 h. The reaction mixture was treatedwith saturated aqueous NaHCO₃ (30 mL) to adjust pH 8 and extracted withEtOAc (50 mL×3). The combined organic layers were concentrated to givethe crude product which was purified with silica gel chromatography(PE/EA=5:1) to give2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyrimidine (230 mg, 15%) asa white solid. ESI-MS [M+H]⁺: 207.8.

Synthesis of 2-(azidomethyl)-6-cyclopropylimidazo[1,2-a]pyrimidine

To a solution of 2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyrimidine(160 mg, 0.77 mmol) in DMF (3 mL) was added NaN₃ (60 mg, 0.92 mmol),then the mixture was stirred at RT for 3 h. H₂O (20 mL) was added to thereaction, extracted with EtOAc (30 mL×3). The combined organic layerswere washed brine, dried over Na₂SO₄, concentrated to give the2-(azidomethyl)-6-cyclopropylimidazo[1,2-a]pyrimidine (162 mg, yield:98%) as a white solid which was used in next step without furtherpurification. ESI-MS [M+H]⁺: 214.9.

Synthesis of Ethyl1-((6-cyclopropylimidazo[1,2-a]pyrimidin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate

To a solution of 2-(azidomethyl)-6-cyclopropylimidazo[1,2-a]pyrimidine(162 mg, 0.75 mmol) in t-BuOH/H₂O (4 mL/4 mL) was added ethyl propiolate(148 mg, 1.51 mmol), CuSO₄ (24 mg, 0.15 mmol) and sodium ascorbate (45mg, 0.23 mmol). The mixture reaction was stirred at RT for 0.5 h. H₂O(30 mL) was added to the reaction, extracted with EtOAc (30 mL×3). Thecombined organic layers were washed with brine, dried over Na₂SO₄,concentrated to give ethyl1-((6-cyclopropylimidazo[1,2-a]pyrimidin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(109 mg, crude) as a white solid, which was used into next step withoutfurther purification. ESI-MS [M+H]⁺: 312.8.

Synthesis of1-((6-cyclopropylimidazo[1,2-a]pyrimidin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicAcid

To a solution of ethyl1-((6-cyclopropylimidazo[1,2-a]pyrimidin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(109 mg, crude) in THF/H₂O (5 mL/2 mL) was added LiOH (16.7 mg, 0.7mmol), then the mixture was stirred at RT for overnight. The reactionwas concentrated to remove THF to give the residue. The pH of theresidue was adjusted with HCl (3 M) to 4. The aqueous layer wasfree-dried to give the1-((6-cyclopropylimidazo[1,2-a]pyrimidin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (130 mg, crude) as a white solid which was used in next stepwithout further purification. ESI-MS [M+H]⁺: 284.9.

Synthesis ofN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyrimidin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(I-165)

To a solution of1-((6-cyclopropylimidazo[1,2-a]pyrimidin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (130 mg, crude) in DMF (3 mL) was added(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride(141 mg, 0.6 mmol), HATU (232 mg, 0.6 mmol) and DIPEA (237 mg, 1.84mmol). The mixture reaction was stirred at RT for 12 h. The mixturereaction was poured into H₂O (30 mL) and yellow solid was precipitatedand filtrated to give N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyrimidin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(77 mg, yield: 20% over 3 steps) as a yellow solid. ESI-MS [M+H]⁺:465.8. Purity: 99.55 (214 nm), 99.25 (254 nm). ¹H NMR (400 MHz, DMSO-d₆)δ 8.71 (s, 2H), 8.58 (s, 1H), 8.44 (s, 2H), 8.21 (d, J=8.0 Hz, 1H), 7.77(s, 1H), 6.76 (t, J=8.0 Hz, 1H), 5.78 (s, 2H), 4.71 (d, J=4.0 Hz, 2H),1.99 (brs, 1H), 0.99-0.97 (m, 2H), 0.77-0.75 (m, 2H).

Example 166

Synthesis of Ethyl2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-carboxylate(I-166a)

To a solution of1-((6-cyclopropyl-8-(ethoxycarbonyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (106 mg, 0.3 mmol),(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride(84 mg, 0.36), HOBT (61 mg, 0.45 mmol) and EDCI (86 mg, 0.45 mmol) inDMF (5 mL) was added DIPEA (194 mg, 1.5 mmol). The resulting reactionwas stirred at RT for 14 h. The reaction was poured into H₂O (100 mL),the white solid was formed. The solid was filtered and washed with DCMto give the ethyl2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-carboxylateas a white solid. (135 mg, yield: 84%). ESI-MS [M+H]⁺: 537.2, purity:95.93 (214 nm), 95.82 (254 nm). ¹H NMR (400 MHz, DMSO-d₆) δ 8.71 (t,J=5.4 Hz, 1H), 8.58-8.56 (m, 2H), 8.44 (d, J=2.3 Hz, 1H), 8.20 (d, J=7.4Hz, 1H), 7.88 (s, 1H), 7.62 (d, J=1.6 Hz, 1H), 6.76 (t, J=6.9 Hz, 1H),5.79 (s, 2H), 4.70 (d, J=5.5 Hz, 2H), 4.34 (q, J=7.1 Hz, 2H), 2.04-1.98(m, 1H), 1.32 (t, J=7.1 Hz, 3H), 1.00-0.93 (m, 2H), 0.72-0.68 (m, 2H).

Synthesis of2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-carboxylicacid (I-166b)

To a solution of ethyl2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-carboxylate(100 mg, 0.19 mmol) in THF/H₂O (8 mL/8 mL) was added LiOH.H₂O (39 mg,0.93 mmol). The reaction was stirred at RT for 3 h. The reaction wasconcentrated in vacuo to give the crude product, which was purified withPrep-HPLC to give the2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-carboxylicacid as a white solid. (50 mg, yield: 51%). ESI-MS [M+H]⁺: 509.1.Purity: 100 (214 nm), 100 (254 nm). ¹H NMR (400 MHz, DMSO-d₆) δ 8.73 (t,J=4.0 Hz, 1H), 8.62 (s, 1H), 8.61 (s, 1H), 8.44 (d, J=2.4 Hz, 1H), 8.20(d, J=4.0 Hz, 1H), 7.96 (s, 1H), 7.70 (d, J=4.0 Hz, 1H), 6.76 (t, J=8.0Hz, 1H), 5.82 (s, 2H), 4.70 (d, J=8.0 Hz, 2H), 2.08-2.00 (m, 1H),0.99-0.95 (m, 2H), 0.74-0.70 (m, 2H)

Example 167

Synthesis ofN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(3-hydroxyoxetan-3-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide

To a solution of1-((8-(3-hydroxyoxetan-3-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (113 mg, 0.32 mmol),(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride(94 mg, 0.4 mmol), HATU (177 mg, 0.47 mmol) in DMF (10 mL) was addedDIPEA (200 mg, 1.55 mmol). The resulting mixture was stirred at RT for14 h. H₂O (30 mL) was added into the reaction, extracted with EtOAC (40mL×3). The combined organic layers were washed with brine, dried overNa₂SO₄, concentrated in vacuo to give the crude product, which waspurified with Prep-TLC (DCM/MeOH=10/1) to give theN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(3-hydroxyoxetan-3-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(60 mg, yield: 35%) as a yellow solid. ESI-MS [M+H]⁺: 537.1.

Synthesis ofN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(3-fluorooxetan-3-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(I-167)

To a solution ofN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(3-hydroxyoxetan-3-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(45 mg, 0.084 mmol) in DCM (8 mL) was added DAST (20 mg, 0.13 mmol) at−78° C. under nitrogen. The resulting mixture was stirred at −78° C.under nitrogen 1 h. The mixture was quenched with NaHCO₃ (aq., 20 mL)and extracted with DCM (30 mL×3). The combined organic layers werewashed with brine, dried over Na₂SO₄, concentrated in vacuo to give thecrude product, which was purified with Prep-TLC combiflash(DCM/MeOH=10/1) to give the compound as a light yellow solid (7 mg,yield: 15%). ESI-MS [M+H]⁺: 539.1. Purity: 95.3 (214 nm), 95.2 (254 nm).¹H NMR (400 MHz, DMSO-d₆) δ 8.72 (t, J=5.4 Hz, 1H), 8.55 (s, 1H),8.49-8.41 (m, 2H), 8.21 (d, J=7.4 Hz, 1H), 7.83 (s, 1H), 7.18 (s, 1H),6.76 (t, J=5.4 Hz, 1H), 5.77 (s, 2H), 5.34-5.25 (m, 2H), 4.99-4.91 (m,2H), 4.70 (d, J=5.4 Hz, 2H), 2.01-1.89 (m, 1H), 0.96-0.91 (m, 2H),0.76-0.67 (m, 2H).

Example 168

Synthesis of(2-(azidomethyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)methanol

The mixture of(2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)methanol (3.0g, 12.6 mmol) and NaN₃ (988 mg, 15.2 mmol) in DMF (40 mL) was stirred atRT for 2 h. The reaction mixture was poured into H₂O (300 mL) andextracted with EtOAc (100 mL×2). The combined organics was washed withbrine, dried over Na₂SO₄, concentrated and dried in vacuo to give(2-(azidomethyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)methanol (2.8g, yield: 91%) as a pale solid. ESI-MS [M+H]⁺: 244.2.

Synthesis of Ethyl1-((6-cyclopropyl-8-(hydroxymethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate

The mixture of(2-(azidomethyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)methanol (2.8g, 11.5 mmol), ethyl propiolate (1.35 g, 13.8 mmol), CuSO₄ (919 mg, 5.76mmol) and sodium ascorbate (1.14 g, 5.76 mmol) in t-BuOH (20 mL) and H₂O(20 mL) was stirred at RT for 3 h. The reaction mixture was poured intoH₂O (100 mL) and the precipitate was collected, and the crude solid waspurified by silica gel chromatography (EA/PE=1/2) to give ethyl1-((6-cyclopropyl-8-(hydroxymethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(3.1 g, yield: 78%) as a yellow solid. ESI-MS [M+H]⁺: 342.2.

Synthesis of1-((6-cyclopropyl-8-(hydroxymethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicAcid

To a solution of ethyl1-((6-cyclopropyl-8-(hydroxymethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(3.1 g, 9.1 mmol) in a mixed solvent of methanol (20 mL), THF (20 mL)and H₂O (10 mL) was added lithium hydroxide monohydrate (756 mg, 18mmol). The mixture was stirred at 40° C. for 1 h. The reaction wasconcentrated to remove THF and MeOH to give the residue. The pH ofresidue was adjusted with 1N HCl to 4 and the yellow solid wasprecipitated. The mixture was filtered and dried in vacuo to give1-((6-cyclopropyl-8-(hydroxymethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (2.6 g, 91%) as a yellow solid. ESI-MS [M+H]⁺: 314.1.

Synthesis ofN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(hydroxymethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide

A mixture of1-((6-cyclopropyl-8-(hydroxymethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (1.0 g, 3.19 mmol),(5-chloro-2-(1H-tetrazol-5-yl)phenyl)methanamine hydrochloride (835 mg,3.83 mmol), EDCI (734 mg, 3.83 mmol), HOBT (518 mg, 3.83 mmol) and DIPEA(1.24 g, 9.57 mmol) in DMF (15 mL) was stirred at 25° C. for 16 h. Thereaction mixture was poured into H₂O (100 mL) and the precipitate wascollected. The crude solid was filtered and purified by silica gelchromatography (DCM/MeOH=20/1) to giveN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(hydroxymethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(1.0 g, yield: 66%) as a pale white solid. ESI-MS [M+H]⁺: 477.1.

Synthesis ofN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((8-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide

To a stirred solution ofN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(hydroxymethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(600 mg, 1.26 mmol) in DCM (20 mL) and THF (10 mL) was added dropwise ofSOCl₂ (1.5 g, 12.6 mmol) at 0° C. The mixture was stirred at RT for 3 h.The reaction mixture was concentrated. The residue was diluted in H₂O(50 mL) and the pH was adjusted to 9-10 with NaHCO₃ aqueous. The mixturewas extracted with EtOAc (100 mL×3), the combined organic layers wereconcentrated purified by silica gel chromatography (DCM/MeOH=20/1) togiveN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((8-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(520 mg, yield: 83%) as a yellow solid. ESI-MS [M+H]⁺: 495.1.

Synthesis of Ethyl3-(2-((4-(((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)-2,2-dimethylpropanote(I-168)

To a stirred solution of ethyl isobutyrate (0.93 g, 8 mmol) in THF (15mL) was added dropwise LDA (4 mL, 2 M in THF) at −40° C. under N₂. After1 h, the solution was added dropwise to the suspension ofN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((8-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(520 mg, 1.05 mmol) in THF (15 mL) at −78° C. The resulting mixture wasstirred for 2 h at −78° C. The reaction mixture was quenched with NH₄Caqueous, extracted with EtOAc (50 mL×3). The combined organics waswashed with brine (100 mL), dried over Na₂SO₄, concentrated and purifiedby silica gel chromatography (DCM/MeOH=20/1) to give ethyl3-(2-((4-(((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)-2,2-dimethylpropanoate(300 mg, yield: 50%) as a white solid. ESI-MS [M+H]⁺: 575.2. Purity:96.39 (214 nm), 97.14 (254 nm). ¹H NMR (400 MHz, DMSO-d₆) δ 8.92 (t,J=5.9 Hz, 1H), 8.51 (s, 1H), 8.34-8.27 (m, 2H), 8.23 (s, 1H), 7.83-7.75(m, 2H), 6.71-6.61 (m, 2H), 5.71 (s, 2H), 4.61 (d, J=5.9 Hz, 2H), 3.93(q, J=7.1 Hz, 2H), 3.08 (s, 2H), 1.92-1.88 (m, 1H), 1.21-1.00 (m, 9H),0.95-0.88 (m, 2H), 0.61 (m, 2H).

Example 169

Synthesis of Ethyl1-((6-cyclopropyl-8-(3-(((methylthio)carbonothioyl)oxy)oxetan-3-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate

To a solution of ethyl1-((6-cyclopropyl-8-(3-hydroxyoxetan-3-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(400 mg, 1.04 mmol) in THF (20 mL) was added NaH (125 mg, 5.20 mmol, 60%in oil) at 0° C. slowly. The resulting mixture was stirred at 0° C. for30 min. Then CS₂ (395 mg, 5.20 mmol) was added at 0° C. After stirringfor 30 min, CH₃I (738 mg, 5.20 mmol) was added and stirred at at 0° C.for 4 h. The reaction was quenched with aqueous NH₄Cl, extracted withEtOAC (50 mL×3). The combined organic layers were washed with brine,dried over Na₂SO₄, concentrated in vacuo to give the ethyl1-((6-cyclopropyl-8-(3-(((methylthio)carbonothioyl)oxy)oxetan-3-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(250 mg crude), which was used into next step without furtherpurification. ESI-MS [M+H]⁺: 474.1

Synthesis of Ethyl1-((8-(oxetan-3-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate

A solution of ethyl1-((6-cyclopropyl-8-(3-(((methylthio)carbonothioyl)oxy)oxetan-3-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(250 mg crude from previous step) and Bu₃SnH (772 mg, 2.64 mmol) andAIBN (87 mg, 0.53 mmol) in toluene (8 mL) was stirred at 125° C. for 0.5h. The reaction was concentrated in vacuo to give the residue, which wasdiluted with H₂O (30 mL), extracted with EtOAc (30 mL×3). The combinedorganic layers were washed with brine, dried over Na₂SO₄, concentratedin vacuo to give the ethyl1-((8-(oxetan-3-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(180 mg, crude). ESI-MS [M+H]⁺: 368.2.

Synthesis of1-((8-(oxetan-3-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicAcid

A mixture of ethyl ethyl1-((8-(oxetan-3-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(180 mg, crude) and LiOH (59 mg, 2.45 mmol) in THF/H₂O (5 mL/5 mL) wasstirred at 50° C. for 3 h. The reaction was concentrated in vacuo togive crude product, which was purified with Prep-HPLC to give the1-((8-(oxetan-3-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (40 mg, yield: 12% over 3 steps) as a yellow solid. ESI-MS [M+H]⁺:340.1

Synthesis ofN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(oxetan-3-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(I-169)

To a solution of1-((8-(oxetan-3-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (20 mg 0.059 mmol),(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride(21 mg, 0.088 mmol), HATU (33 mg, 0.088 mmol) in DMF (10 mL) was addedDIPEA (23 mg, 0.177 mmol). The resulting mixture was stirred at RT for14 h. H₂O (30 mL) was added into the reaction, extracted with EtOAC (30mL×3). The combined organic layers were washed with brine, dried overNa₂SO₄, concentrated in vacuo to give the crude product, which waspurified with Prep-TLC (DCM/MeOH=10/1) to give theN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(oxetan-3-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(15 mg, yield: 49%) as a white solid. ESI-MS [M+H]⁺: 521.1. Purity: 97.8(214 nm), 97.7 (254 nm). ¹H NMR (400 MHz, DMSO-d₆) δ 8.78-8.71 (m, 1H),8.55 (s, 1H), 8.45 (s, 1H), 8.34-8.32 (m, 1H), 8.21 (d, J=7.4 Hz, 1H),7.91 (s, 1H), 7.28-7.20 (m, 1H), 6.81-6.71 (m, 1H), 5.78 (s, 2H),4.98-4.89 (m, 2H), 4.84-4.76 (m, 2H), 4.72-4.59 (m, 3H), 2.05-1.98 (m,1H), 0.98-0.94 (m, 2H), 0.79-0.72 (m, 2H).

Example 170

Synthesis of3-(2-((4-(((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)-2,2-dimethylpropanoicAcid (I-170)

To a solution of ethyl3-(2-((4-(((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)-2,2-dimethylpropanoate(120 mg, 0.21 mmol) in MeOH (6 mL), THF (6 mL) and H₂O (4 mL) was addedNaOH (167 mg, 4.18 mmol). The mixture was stirred at 40° C. for 10 h.MeOH and THF was removed and the mixture was diluted in H₂O (40 mL),extracted with EtOAc (40 mL). The organic layer was discarded. The pH ofaqueous layer was acidified to 5-6 and extracted with DCM/MeOH (10/1, 30mL×2). The combined organics was washed with brine, dried over Na₂SO₄,concentrated and purified by silica gel chromatography (DCM/MeOH=10/1)to give3-(2-((4-(((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)-2,2-dimethylpropanoicacid (35 mg, yield: 30%) as a white solid. ESI-MS [M+H]⁺: 547.2. Purity:99.05 (214 nm), 98.36 (254 nm). ¹H NMR (400 MHz, DMSO-d₆) δ 12.33 (s,1H), 8.91 (t, J=5.9 Hz, 1H), 8.52 (s, 1H), 8.36-8.27 (m, 2H), 8.21 (s,1H), 7.86-7.80 (m, 1H), 7.76 (s, 1H), 6.74 (s, 1H), 6.64 (dd, J=7.5, 2.1Hz, 1H), 5.72 (s, 2H), 4.61 (d, J=5.9 Hz, 2H), 3.09 (s, 2H), 1.90-1.83(m, 1H), 1.05 (s, 6H), 0.94-0.87 (m, 2H), 0.66-0.58 (m, 2H).

Example 171

Synthesis of 5-cyclopropyl-3-fluoropyridin-2-amine

A mixture of 5-chloro-3-fluoropyridin-2-amine (2 g, 13.65 mmol),cyclopropylboronic acid (1.76 g, 20.47 mmol), Pd(OAc)₂ (306 mg, 1.365mmol), SPhos (1.12 g, 2.73 mmol) and K₃PO₄ (10.14 g, 47.78 mmol) intoluene (40 mL) and H₂O (10 mL) was stirred at 90° C. for 16 h under N₂.The reaction mixture was filtered and washed with EtOAc. The combinedfiltrate was washed with H₂O (100 mL) and brine (100 mL), dried overNa₂SO₄, concentrated and purified by silica gel chromatography(EA/PE=1/2) to give 5-cyclopropyl-3-fluoropyridin-2-amine (2.2 g, yield:100%) as a yellow syrup. ESI-MS [M+H]⁺: 153.2.

Synthesis of2-(chloromethyl)-6-cyclopropyl-8-fluoroimidazo[1,2-a]pyridine

A mixture of 5-cyclopropyl-3-fluoropyridin-2-amine (2.2 g, 13.65 mmol)and 1,3-dichloropropan-2-one (5.5 g, 43.38 mmol) in EtOH (40 mL) wasstirred at 85° C. for 16 h. The reaction mixture was concentrated. Theresidue was washed with NaHCO₃ aqueous solution and extracted with EtOAc(100 mL×3). The organic layers were washed with brine (100 mL), driedover Na₂SO₄, concentrated and purified by silica gel chromatography(EA/PE=1/2) to give2-(chloromethyl)-6-cyclopropyl-8-fluoroimidazo[1,2-a]pyridine (1.8 g,58%) as a yellow solid. ESI-MS [M+H]⁺: 225.1.

Synthesis of2-(azidomethyl)-6-cyclopropyl-8-fluoroimidazo[1,2-a]pyridine

A mixture of2-(chloromethyl)-6-cyclopropyl-8-fluoroimidazo[1,2-a]pyridine (1.8 g,8.01 mmol) and NaN₃ (625 mg, 9.61 mmol) in DMF (20 mL) was stirred at RTfor 3 h. The reaction mixture was poured into H₂O (100 mL) and extractedwith EtOAc (80 mL×2). The combined organics was washed with brine (160mL), concentrated and dried in vacuo to give2-(azidomethyl)-6-cyclopropyl-8-fluoroimidazo[1,2-a]pyridine (1.75 g,yield: 95%) as a white solid. ESI-MS [M+H]⁺: 232.1.

Synthesis of Ethyl1-((6-cyclopropyl-8-fluoroimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate

A mixture of2-(azidomethyl)-6-cyclopropyl-8-fluoroimidazo[1,2-a]pyridine (1.75 g,7.57 mmol), ethyl propiolate (891 mg, 9.08 mmol), CuSO₄ (362 mg, 2.27mmol) and sodium ascorbate (750 mg, 3.79 mmol) in t-BuOH (20 mL) and H₂O(20 mL) was stirred at RT for 3 h. H₂O (50 mL) was added to thereaction, extracted with EtOAc (100 mL×3). The combined organics werewashed with brine (100 mL), dried over Na₂SO₄, concentrated to give thecrude product, which was purified by silica gel chromatography(EA/PE=1/2) to give ethyl1-((6-cyclopropyl-8-fluoroimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(1.0 g, yield: 40%) as a white solid. ESI-MS [M+H]⁺: 330.1.

Synthesis of1-((6-cyclopropyl-8-fluoroimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicAcid

To a solution of ethyl1-((6-cyclopropyl-8-fluoroimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(270 mg, 0.82 mmol) in methanol (4 mL), THF (4 mL) and H₂O (2 mL) wasadded lithium hydroxide monohydrate (138 mg, 3.28 mmol). The mixture wasstirred at 40° C. for 2 h. MeOH and THF was removed. The residue wasdiluted in H₂O (20 mL), the pH was acidified to 5-6 by HCl (1N) andyellow solid was precipitated. The mixture was filtered and dried invacuo to give1-((6-cyclopropyl-8-fluoroimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (220 mg, 89%) as a yellow solid. ESI-MS [M+H]⁺: 302.1.

Synthesis ofN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-fluoroimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(I-171)

A mixture of1-((6-cyclopropyl-8-fluoroimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (64 mg, 0.212 mmol),(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride(50 mg, 0.212 mmol), EDCI (49 mg, 0.254 mmol), HOBT (34 mg, 0.254 mmol)and DIPEA (82 mg, 0.636 mmol) in DMF (3 mL) was stirred at 25° C. for 16h. The reaction mixture was poured into H₂O (40 mL) and the yellow solidwas precipitate. The mixture was filtered and washed with MeOH (30 mL),dried in vacuo to giveN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-fluoroimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(75 mg, yield: 74%) as a pale white solid. ESI-MS [M+H]⁺: 483.1. Purity:99.62 (214 nm), 100 (254 nm). ¹H NMR (400 MHz, DMSO-d₆) δ 8.71 (t, J=5.2Hz, 1H), 8.57 (s, 1H), 8.44 (d, J=2.2 Hz, 1H), 8.27 (s, 1H), 8.21 (d,J=7.4 Hz, 1H), 7.95 (d, J=2.7 Hz, 1H), 6.95 (d, J=12.4 Hz, 1H), 6.76 (t,J=6.9 Hz, 1H), 5.76 (s, 2H), 4.70 (d, J=5.4 Hz, 2H), 1.98-1.90 (m, 1H),0.98-0.88 (m, 2H), 0.75-0.65 (m, 2H).

Example 172

Synthesis of 5-chloro-6-methylpyridin-2-amine

To a solution of 6-methylpyridin-2-amine (1.08 g, 1 mmol) in DMF (10 mL)was added NCS (1.34 g, 1 mmol), then the mixture was stirred at RT for12 h. The mixture was treated with ice H₂O and extracted with EtOAc (100mL). The organic layer was washed with brine, dried over Na₂SO₄,concentrated to give the crude product which was purified with silicagel chromatography (PE/EA=2:1) to give 5-chloro-6-methylpyridin-2-amineas a yellow solid (750 mg, yield: 53%). ESI-MS [M+H]⁺: 142.9.

Synthesis of 6-chloro-2-(chloromethyl)-5-methylimidazo[1,2-a]pyridine

To a solution of 5-chloro-6-methylpyridin-2-amine (500 mg, 3.51 mmol) inDME (20 mL) was added 1,3-dichloropropan-2-one (667 mg, 5.26 mmol), thenthe mixture was stirred at 90° C. for overnight. The mixture was treatedwith NaHCO₃ to adjust pH 8 and extracted with EtOAc (100 mL×3). Theorganic layers were washed with brine, dried over Na₂SO₄, concentratedto give the crude product which was purified with silica gelchromatography (EA/DCM=1:5) to give6-chloro-2-(chloromethyl)-5-methylimidazo[1,2-a]pyridine (357 mg, yield:47%) as white oil. ESI-MS [M+H]⁺: 214.9.

Synthesis of 2-(azidomethyl)-6-chloro-5-methylimidazo[1,2-a]pyridine

To a solution of6-chloro-2-(chloromethyl)-5-methylimidazo[1,2-a]pyridine (158 mg, 0.73mmol) in DMF (3 mL) was added NaN₃ (48 mg, 0.73 mmol). And the mixturereaction was stirred at RT for 5 h. H₂O (50 mL) was added to reaction,extracted with EtOAc (50 mL×3). The combined organic layers were washedwith brine, dried over Na₂SO₄, concentrated to give the2-(azidomethyl)-6-chloro-5-methylimidazo[1,2-a]pyridine (155 mg, yield:95%) as a yellow solid. ESI-MS [M+H]⁺: 221.8.

Synthesis of Ethyl1-((6-chloro-5-methylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate

To a solution of 2-(azidomethyl)-6-chloro-5-methylimidazo[1,2-a]pyridine(155 mg, 0.7 mmol) in t-BuOH/H₂O (3 mL/3 mL) was added ethyl propiolate(137 mg, 1.4 mmol), CuSO₄ (22 mg, 0.14 mmol) and sodium ascorbate (42mg, 0.21 mmol). And the resulting mixture was stirred at RT for 1 h. H₂O(20 mL) was added to the reaction, extracted with EtOAc (50 mL×3). Thecombined organic layers were washed with brine, dried over Na₂SO₄,concentrated to give ethyl1-((6-chloro-5-methylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(220 mg, crude) as a yellow solid. ESI-MS [M+H]⁺: 319.9.

Synthesis of1-((6-chloro-5-methylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicAcid

To a solution of ethyl1-((6-chloro-5-methylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(220 mg, crude) in THF/H₂O (5 mL/2 mL) was added LiOH (33 mg, 1.38mmol), then the mixture was stirred at RT overnight. The mixture wastreated with HCl (aq) to adjust pH 4 and the yellow solid wasprecipitated. The mixture was filtered, washed with H₂O (10 mL) anddried to give the 1-((6-chloro-5-methylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid (100 mg, yield: 50% over 2steps) as a yellow solid. ESI-MS [M+H]⁺: 291.9.

Synthesis of1-((6-chloro-5-methylimidazo[1,2-a]pyridin-2-yl)methyl)-N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(I-172)

To a solution of1-((6-chloro-5-methylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (100 mg, 0.34 mmol) in DMF (2 mL) was added(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride(160 mg, 0.68 mmol), HATU (261 mg, 0.68 mmol) and DIPEA (265 mg, 2.06mmol). The mixture reaction was stirred at RT for 12 h. H₂O (20 mL) wasadded to the reaction, extracted with EtOAc (30 mL×3). The combinedorganic layers were washed with brine, dried over Na₂SO₄, concentratedto give the crude product, which was purified with Prep-HPLC to give1-((6-chloro-5-methylimidazo[1,2-a]pyridin-2-yl)methyl)-N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(137 mg, 84%) as a white solid. ESI-MS [M+H]⁺: 472.5. Purity: 99.69 (214nm), 99.83 (254 nm). ¹H NMR (400 MHz, DMSO-d₆) δ 8.69 (t, J=8.0 Hz, 1H),8.57 (s, 1H), 8.44 (s, 1H), 8.21 (d, J=8.0 Hz, 1H), 8.03 (s, 1H), 7.49(d, J=8.0 Hz, 1H), 7.37 (d, J=12.0 Hz, 1H), 6.76 (t, J=8.0 Hz, 1H), 5.79(s, 2H), 4.71 (d, J=4.0 Hz, 2H), 2.68 (s, 3H).

Example 173

Synthesis of tert-butyl1-((6-cyclopropyl-8-morpholinoimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate

To a solution of To a solution of tert-butyl1-((8-bromo-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(0.2 g, 0.48 mmol) and morpholine (0.05 g, 0.6 mmol) in toluene (20 mL)and H₂O (2 mL) was added CsCO₃ (0.4 g, 1.2 mmol), XPhos (0.04 g, 0.08mmol) and Pd₂(dba)₃ (0.04 g, 0.04 mmol). After the mixture was stirredat 120° C. for 12 h under N₂, H₂O (100 mL) was added and extracted withEtOAc (20 mL*3). The combined organic layers were concentrated andpurified by silica gel chromatography (DCM/MeOH=20/1) to give tert-butyl1-((6-cyclopropyl-8-morpholinoimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(0.13 g, yield: 65%) as a yellow solid. ESI-MS [M+H]⁺: 425.3.

Synthesis of1-((6-cyclopropyl-8-morpholinoimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicAcid

To a solution of tert-butyl1-((6-cyclopropyl-8-morpholinoimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(0.13 g, 0.3 mmol) in DCM (10 mL) was added TFA (2 mL). The mixture wasstirred at 25° C. for 3 h. The solvent was removed by vacuo to give thecrude1-((6-cyclopropyl-8-morpholinoimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (0.1 g, yield: 90.9%) as a black solid which was used into nextstep without purification. ESI-MS [M+H]⁺: 369.1.

Synthesis ofN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-morpholinoimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(I-173)

A solution of1-((6-cyclopropyl-8-morpholinoimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (0.1 g, 0.27 mmol),(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride(0.082 g, 0.35 mmol), HATU (0.17 g, 0.45 mmol) and DIPEA (0.12 g, 0.9mmol) in DMF (5 mL) was stirred at 25° C. for 16 h. The solvent wasremoved by vacuo to give the crude and purified by Prep-HPLC to giveN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-morpholinoimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(70 mg, yield: 46.7%) as a white solid. ESI-MS [M+H]⁺: 550.2. Purity:100.00 (214 nm), 100.00 (254 nm). ¹H NMR (400 MHz, DMSO-d₆) δ 8.70 (s,1H), 8.52 (s, 1H), 8.44 (s, 1H), 8.20 (d, J=7.3 Hz, 1H), 7.94 (d, J=10.2Hz, 1H), 7.72 (s, 1H), 6.76 (t, J=6.9 Hz, 1H), 6.20 (s, 1H), 5.71 (s,2H), 4.69 (d, J=5.0 Hz, 2H), 3.76 (s, 3H), 3.43 (s, 3H), 2.89 (s, 1H),2.73 (s, 1H), 1.79-1.99 (m, 1H), 0.88 (d, J=7.2 Hz, 2H), 0.67 (d, J=4.4Hz, 2H).

Example 174

Synthesis of tert-butyl1-((8-cyano-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate

A mixture of tert-butyl1-((8-bromo-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(800 mg, 1.91 mmol), Zn(CN)2 (289 mg, 2.48 mmol) and Pd(PPh3)4 (553 mg,0.47 mmol) in DMF (10 mL) was stirred at 100° C. for 2 h. Water (20 mL)was added and extracted with EtOAc (100 mL*3). The combined organicswere concentrated and purified by silica gel chromatography (EA/PE=3/10)to give tert-butyl1-((8-cyano-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(650 mg, yield: 93%) as a white solid. ESI-MS [M+H]⁺: 365.1

Synthesis of tert-butyl1-((6-cyclopropyl-8-(2H-tetrazol-5-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate

To a solution of tert-butyl1-((8-cyano-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(650 mg, 1.78 mmol) and NH₄Cl (942 mg, 17.8 mmol) in DMF (10 mL) wasadded NaN3 (1.1 g, 17.8 mmol). After the mixture was stirred at 25° C.for 5 h, H₂O (100 mL) was added and extracted with EtOAc (100 mL*3). Thecombined organic layers were concentrated and purified by silica gelchromatography (EA/PE=3/10) to tert-butyl1-((6-cyclopropyl-8-(2H-tetrazol-5-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(300 mg, yield: 41.3%) as a yellow solid. ESI-MS [M+H]⁺: 408.1

Synthesis of1-((6-cyclopropyl-8-(2H-tetrazol-5-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicAcid

A solution of tert-butyl1-((6-cyclopropyl-8-(2H-tetrazol-5-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(300 mg, 0.73 mmol) in TFA/DCM (1.6 mL/4.8 mL) was stirred at 25° C. for2 h. The mixture was concentrated to give the crude (250 mg, yield: 83%)as a yellow oil which was used into next step without purification.ESI-MS [M+H]⁺: 352.1

Synthesis ofN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(2H-tetrazol-5-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(I-174)

To a solution of1-((6-cyclopropyl-8-(2H-tetrazol-5-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (250 mg, 0.71 mmol),(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride(190 mg, 0.81 mmol), HATU (404 mg, 1.0 mmol) in DMF (3 mL) was addedDIPEA (458 mg, 3.5 mmol. After the mixture was stirred at 25° C. for 16h, solvent was concentrated and purified by Prep-HPLC to giveN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(2H-tetrazol-5-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(15.6 mg, yield: 4.1%) as a white solid. ESI-MS [M+H]⁺: 533.1. Purity:97.16 (214 nm), 99.14 (254 nm). ¹H NMR (400 MHz, DMSO-d₆) 8.88 (s, 1H),8.68 (t, J=5.4 Hz, 1H), 8.60 (s, 1H), 8.43 (d, J=2.4 Hz, 1H), 8.19 (d,J=7.4 Hz, 1H), 8.04 (s, 1H), 7.90 (s, 1H), 6.79-6.71 (m, 1H), 5.83 (s,2H), 4.70 (d, J=5.5 Hz, 2H), 2.16-2.05 (m, 1H), 1.03-0.96 (m, 2H),0.81-0.74 (m, 2H).

Example 175

Synthesis of 4-cyclopropylpyridine

A mixture of 4-bromopyridine hydrochloride (21 g, 108 mmol),cyclopropylboronic acid (13.9 g, 162 mmol), PdCl₂(dppf) (3.95 g, 5.4mmol) and K₂CO₃ (4.78 g, 324 mmol) in 1,4-dioxane (200 mL) and H₂O (50mL) was stirred at 90° C. for 16 h under N₂. The reaction mixture wasfiltered through celite and 1,4-dioxane was removed. The residue wasdiluted with H₂O (100 mL) and extracted with EtOAc (100 mL×3). Thecombined organics was washed with brine (200 mL×1), dried over Na₂SO₄,concentrated and purified by silica gel chromatography (EtOAc/PE=1/2) togive 4-cyclopropylpyridine (10 g, yield: 78%) as light brown oil. ESI-MS[M+H]⁺: 120.2.

Synthesis of 1-amino-4-cyclopropylpyridin-1-ium2,4,6-trimethylbenzenesulfonate

To a stirred solution of 4-cyclopropylpyridine (8.7 g, 73 mmol) in DCM(100 mL) was added slowly a solution of O-(mesitylsulfonyl)hydroxylamine(15.7 g, 73 mmol) in DCM (50 mL) at 0° C. The mixture was stirred at 0°C. for 10 min and warmed to RT and stirred for 2 h. The reaction mixturewas concentrated and dried in vacuo to give1-amino-4-cyclopropylpyridin-1-ium 2,4,6-trimethylbenzenesulfonate (24.4g, yield: 100%) as a yellow solid. ESI-MS [M+H]⁺: 135.2.

Synthesis of dimethyl5-cyclopropylpyrazolo[1,5-a]pyridine-2,3-dicarboxylate

To a stirred solution of 1-amino-4-cyclopropylpyridin-1-ium2,4,6-trimethylbenzenesulfonate (24.4 g, 73 mmol) and dimethylbut-2-ynedioate (20.75 g, 146 mmol) in acetonitrile (250 mL) was addeddropwise of DBU (22.23 g, 146 mmol) at 0° C. The mixture was stirred atRT for 16 h and stirred at 75° C. for 2 h. The reaction mixture wasconcentrated and purified by silica gel chromatography (EA/PE=1/3) togive dimethyl 5-cyclopropylpyrazolo[1,5-a]pyridine-2,3-dicarboxylate(6.0 g, yield: 30%) as a yellow solid. ESI-MS [M+H]⁺: 275.1.

Synthesis of 5-cyclopropylpyrazolo[1,5-a]pyridine-2-carboxylic Acid

A mixture of dimethyl5-cyclopropylpyrazolo[1,5-a]pyridine-2,3-dicarboxylate (6 g, 21.88 mmol)in 50% H₂SO₄ (30 mL) and 1,4-dioxane (40 mL) was stirred at 85° C. for 5h. The reaction mixture was poured into H₂O (300 mL) and extracted withEtOAc/MeOH (10:1, 150 mL×3). The combined organics was washed with brine(400 mL×1), dried over Na₂SO₄, concentrated and dried in vacuo to give5-cyclopropylpyrazolo[1,5-a]pyridine-2-carboxylic acid (3.6 g, yield:81%) as a light brown solid. ESI-MS [M+H]⁺: 203.1.

Synthesis of (5-cyclopropylpyrazolo[1,5-a]pyridin-2-yl)methanol

To a stirred suspension of LiAlH₄ (788 mg, 20.76 mmol) in THF (40 mL)was added dropwise the solution of5-cyclopropylpyrazolo[1,5-a]pyridine-2-carboxylic acid (1.4 g, 6.92mmol) in THF (30 mL) at 0° C. The mixture was stirred at RT for 4 h. Thereaction mixture was quenched by adding H₂O (1 mL), 15% NaOH aqueous (1mL) and H₂O (3 mL). The mixture was stirred for 30 min at 0° C. and thenfiltered and the filtrate was concentrated and purified by silica gelchromatography (EA/PE=1/1) to give(5-cyclopropylpyrazolo[1,5-a]pyridin-2-yl)methanol (350 mg, yield: 27%)as a yellow solid. ESI-MS [M+H]⁺: 189.2.

Synthesis of 2-(chloromethyl)-5-cyclopropylpyrazolo[1,5-a]pyridine

To a stirred solution of(5-cyclopropylpyrazolo[1,5-a]pyridin-2-yl)methanol (350 mg, 1.86 mmol)in DCM (10 mL) was added SOCl₂ (2.21 g, 18.6 mmol) at 0° C. The mixturewas stirred at RT for 6 h. The reaction mixture was concentrated to give2-(chloromethyl)-5-cyclopropylpyrazolo[1,5-a]pyridine (350 mg, yield:91%) as a yellow solid which was used into next step withoutpurification. ESI-MS [M+H]⁺: 207.1.

Synthesis of 2-(azidomethyl)-5-cyclopropylpyrazolo[1,5-a]pyridine

A mixture of 2-(chloromethyl)-5-cyclopropylpyrazolo[1,5-a]pyridine (350mg, 1.69 mmol) and NaN₃ (132 mg, 2.03 mmol) in DMF (5 mL) was stirred atRT for 2 h. Water (50 mL) was added and extracted with EtOAc (50 mL×2).The combined organics was washed with brine (80 mL×3), concentrated anddried in vacuo to give2-(azidomethyl)-5-cyclopropylpyrazolo[1,5-a]pyridine (360 mg, yield:100%) as a yellow syrup. ESI-MS [M+H]⁺: 214.2.

Synthesis of Ethyl1-((5-cyclopropylpyrazolo[1,5-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate

The mixture of 2-(azidomethyl)-5-cyclopropylpyrazolo[1,5-a]pyridine (360mg, 1.69 mmol), ethyl propiolate (199 mg, 2.03 mmol), CuSO₄ (135 mg,0.845 mmol) and sodium ascorbate (167 mg, 0.845 mmol) in t-BuOH (5 mL)and H₂O (5 mL) was stirred at RT for 3 h. The reaction mixture wasconcentrated. The residue was diluted in H₂O (50 mL) and extracted withEtOAc (50 mL×3). The combined organics were washed with brine (80 mL×1),dried over Na₂SO₄, concentrated and purified by silica gelchromatography (EA/PE=1/1) to give ethyl1-((5-cyclopropylpyrazolo[1,5-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(160 mg, yield: 30%) as a yellow solid. ESI-MS [M+H]⁺: 312.2.

Synthesis of1-((5-cyclopropylpyrazolo[1,5-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicAcid

A solution of ethyl1-((5-cyclopropylpyrazolo[1,5-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(160 mg, 0.51 mmol) in a mixed solvent of methanol (2 mL), THF (2 mL)and H₂O (1 mL) was added lithium hydroxide monohydrate (86 mg, 2.04mmol). The mixture was stirred at 40° C. for 1 h. Most of the solventwas removed and the residue was diluted with H₂O (5 mL), the pH value ofmixture was adjusted to 4-5 by adding HCl aqueous (1 M). The precipitatewas collected and dried to give1-((5-cyclopropylpyrazolo[1,5-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (120 mg, 83%) as a yellow solid. ESI-MS [M+H]⁺: 284.2.

Synthesis ofN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((5-cyclopropylpyrazolo[1,5-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(I-175)

A mixture of1-((5-cyclopropylpyrazolo[1,5-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (54 mg, 0.191 mmol),(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride(45 mg, 0.191 mmol), EDCI (55 mg, 0.287 mmol), HOBT (39 mg, 0.287 mmol)and DIPEA (123 mg, 0.955 mmol) in DMF (3 mL) was stirred at 25° C. for16 h. The reaction mixture was poured into H₂O (30 mL) and theprecipitate was collected, washed with H₂O (30 mL), dried in vacuo togiveN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((5-cyclopropylpyrazolo[1,5-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(65 mg, yield: 73%) as a pale white solid. ESI-MS [M+H]⁺: 465.1. Purity:99.85 (214 nm), 100 (254 nm). ¹H NMR (400 MHz, DMSO-d₆) δ 8.72 (t, J=5.3Hz, 1H), 8.60 (s, 1H), 8.49 (d, J=7.2 Hz, 1H), 8.44 (d, J=2.3 Hz, 1H),8.21 (d, J=7.4 Hz, 1H), 7.35 (s, 1H), 6.76 (t, J=6.9 Hz, 1H), 6.59 (dd,J=7.3, 1.8 Hz, 1H), 6.38 (s, 1H), 5.80 (s, 2H), 4.70 (d, J=5.5 Hz, 2H),2.01-1.93 (m, 1H), 1.03-0.94 (m, 2H), 0.79-0.71 (m, 2H).

Example 176

Synthesis of6-cyclopropyl-2-(3-(trimethylsilyl)prop-2-yn-1-yl)imidazo[1,2-a]pyridine

A mixture of 2-(bromomethyl)-6-cyclopropylimidazo[1,2-a]pyridine (1.0 g,4 mmol), ethynyltrimethylsilane (1.2 g, 12 mmol), Cu (153 mg, 0.8 mmol),TBAI (295 mg, 0.8 mmol) and K₂CO₃ (2.75 g, 20 mmol) in DMEF (10 mL) wasstirred at 45° C. for 16 h. The reaction was quenched with H₂O (100 mL)and extracted with EtOAc (100 mL×5). The combined organic layers werewashed with brine, dried over Na₂SO₄, concentrated in vacuum to give thecrude product which was purified by silica gel (eluent: EtOAc/PE: 1/5 to1/1) to give6-cyclopropyl-2-(3-(trimethylsilyl)prop-2-yn-1-yl)imidazo[1,2-a]pyridine(270 mg, yield: 25%) as a yellow oil. ESI-MS [M+H]⁺: 269.1.

Synthesis of 6-cyclopropyl-2-(prop-2-yn-1-yl)imidazo[1,2-a]pyridine

To a solution of6-cyclopropyl-2-(3-(trimethylsilyl)prop-2-yn-1-yl)imidazo[1,2-a]pyridine(269 mg, 1.0 mmol) in MeOH (5 mL) was added K₂CO₃ (690 mg, 5 mmol). Themixture was stirred at RT for 2 h. The reaction was monitored by LCMSuntil the starting material consumed. Water (50 mL) was added andextracted with EtOAc (50 mL×3). The combined organic layers were washedwith brine, dried over Na₂SO₄, concentrated in vacuo to give the crudeproduct which was purified by silica gel (eluent: DCM/MeOH: 50/1 to10/1) to give 6-cyclopropyl-2-(prop-2-yn-1-yl)imidazo[1,2-a]pyridine(158 mg, yield: 80%) as a yellow oil. ESI-MS [M+H]⁺: 197.1.

Synthesis of Ethyl5-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)isoxazole-3-carboxylate

To a solution of 6-cyclopropyl-2-(prop-2-yn-1-yl)imidazo[1,2-a]pyridine(158 mg, 0.8 mmol) and ethyl 2-chloro-2-(hydroxyimino)acetate (606 mg,4.0 mmol) in Et₂O (3 mL) was added TEA (485 mg, 4.8 mmol). The mixturewas stirred at RT for 16 h. The reaction was quenched with H₂O (30 mL)and extracted with EtOAc (50 mL×3). The combined organic layers werewashed with brine, dried over Na₂SO₄, concentrated in vacuo to give thecrude product, which was purified by Prep-TLC (DCM/MeOH=20/1) to giveethyl5-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)isoxazole-3-carboxylate(30 mg, yield: 12%) as a white solid. ESI-MS [M+H]⁺: 312.2.

Synthesis of lithium5-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)isoxazole-3-carboxylate

To a mixture of ethyl5-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)isoxazole-3-carboxylate(30 mg, 0.1 mmol) in MeOH/THF/H₂O (1 mL/1 mL/1 mL) was added LiOH.H₂O(13 mg, 0.3 mmol). The mixture was stirred at RT for 3 h. The reactionwas monitored by LCMS until the starting material consumed. The reactionwas freeze-dried to give the crude lithium5-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)isoxazole-3-carboxylate(50 mg) as a yellow solid. ESI-MS [M+H]⁺: 284.1.

Synthesis ofN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-5-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)isoxazole-3-carboxamide(I-176)

To a mixture of lithium5-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)isoxazole-3-carboxylate(50 mg, crude from last step),(7-chloroimidazo[1,5-a]pyridin-1-yl)methanamine HCl salt (33 mg, 0.15mmol) and DIPEA (65 mg, 0.65 mmol) in DMF (1 mL) was added HOBT (27 mg,0.2 mmol) and EDCI (38 mg, 0.2 mmol). The mixture was stirred at RT for48 h. The reaction was quenched with H₂O (10 mL) and extracted withEtOAc (30 mL×3). The combined organic layers were washed with brine,dried over Na₂SO₄, concentrated in vacuo to give the crude product whichwas purified by Pre-TLC (DCM/MeOH=10/1) to giveN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-5-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)isoxazole-3-carboxamide(2.5 mg, yield: 5.6% over 2 steps) as a white solid. ESI-MS [M+H]⁺:447.0. Purity: 89.9 (214 nm), 88.6 (254 nm). ¹H NMR (400 MHz, DMSO-d₆) δ9.18 (t, J=5.8 Hz, 1H), 8.37-8.28 (m, 3H), 7.82 (d, J=1.8 Hz, 1H), 7.70(s, 1H), 7.38 (d, J=9.3 Hz, 1H), 6.97 (dd, J=9.3, 1.8 Hz, 1H), 6.66 (dd,J=7.5, 2.1 Hz, 1H), 6.59 (s, 1H), 4.60 (d, J=5.9 Hz, 2H), 4.27 (s, 2H),1.96-1.89 (m, 1H), 0.94-0.87 (m, 2H), 0.71-0.64 (m, 2H).

Example 177

Synthesis of 2-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)acetic Acid

To a solution of ethyl2-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)acetate (770 mg, 3.15 mmol)in MeOH (8 mL) and THF (8 mL) was added a solution of LiOH.H₂O (398 mg,9.45 mmol) in H₂O (8 mL). The mixture was stirred at RT for 2 h. Thevolatile was removed in vacuo and the aqueous phase was acidified to pH4-5 with 2N HCl, and concentrated to get the crude product which waspurified by flash column chromatography (0-10% MeOH in DCM) to get2-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)acetic acid (440 mg, yield:65%) as a dark yellow solid. ESI-MS [M+H]⁺: 216.9.

Synthesis of Ethyl5-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1,2,4-oxadiazole-3-carboxylate

To a solution of 2-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)acetic acid(300 mg, 1.39 mmol) in DMF (8 mL) was added CDI (270 mg, 1.67 mmol). Theresulting mixture was stirred at RT for 1 h. To the mixture was addedethyl 2-(hydroxyamino)-2-iminoacetate (238 mg, 1.81 mmol). The resultingmixture was stirred at 50° C. for 3 h. To the mixture was added TBAF(1.4 mL, 1 M). The resulting mixture was stirred at 90° C. overnight.The reaction mixture was concentrated. The residue was partitionedbetween DCM (20 mL) and H₂O (15 mL). The layers were separated and theaqueous phase was extracted with DCM (2×15 mL). The combined organiclayers were washed with brine (15 mL), dried over Na₂SO₄, filtered andconcentrated. The residue was purified by flash column chromatography(0-10% MeOH in DCM) to get ethyl5-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1,2,4-oxadiazole-3-carboxylate(200 mg, yield: 46%) as a brown oil. ESI-MS [M+H]⁺: 313.0.

Synthesis of5-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1,2,4-oxadiazole-3-carboxylicAcid

To a solution of ethyl5-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1,2,4-oxadiazole-3-carboxylate(200 mg, 0.64 mmol) in THF (10 mL) was added a solution of NaOH (38 mg,0.96 mmol) in H₂O (10 mL). The mixture was stirred at RT for 3 h. Thevolatile was removed in vacuo and the aqueous phase was extracted withDCM (2×15 mL). The aqueous phase was acidified to pH 4-5 with 2N HCl,and lyophilized to get5-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1,2,4-oxadiazole-3-carboxylicacid (200 mg, crude) as a dark yellow solid. ESI-MS [M+H]⁺: 285.2.

Synthesis of Methyl5-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1,2,4-oxadiazole-3-carboxylate

To a solution of5-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1,2,4-oxadiazole-3-carboxylicacid (200 mg, crude) in MeOH (3 mL) was added SOCl2 (67 mg, 0.56 mmol).The resulting mixture was stirred at 55° C. overnight. The reactionmixture was concentrated. The residue was partitioned between DCM (20mL) and aqueous saturated NaHCO₃ solution (20 mL). The layers wereseparated and the aqueous phase was extracted with DCM (2×20 mL). Thecombined organic layers were washed with brine (30 mL), dried overNa₂SO₄, filtered and concentrated to get methyl5-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1,2,4-oxadiazole-3-carboxylate(60 mg, yield: 32%) as an orange solid. The crude product was used fornext step directly without purification. ESI-MS [M+H]⁺: 299.0.

Synthesis ofN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-5-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1,2,4-oxadiazole-3-carboxamide(I-177)

To a mixture of methyl5-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1,2,4-oxadiazole-3-carboxylate(60 mg, 0.20) and (7-chloroimidazo[1,5-a]pyridin-1-yl)methanaminehydrochloride (44 mg, 0.22 mmol) in MeOH (3 mL) was added DIPEA (52 mg,0.4 mmol). The resulting mixture was stirred under reflux for 25 h. Thereaction mixture was concentrated. The residue was partitioned betweenDCM (10 mL) and H₂O (10 mL). The layers were separated and the aqueousphase was extracted with DCM (2×20 mL). The combined organic phase waswashed with brine (10 mL), dried over Na₂SO₄, filtered and concentratedto get the crude product. The crude product was purified by flash columnchromatography (0-10% MeOH in DCM) and then prep-TLC (DCM/MeOH=17/1) togetN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-5-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1,2,4-oxadiazole-3-carboxamide(10 mg, yield: 11.1%) as a yellow solid. ESI-MS [M+H]⁺: 448.0. Purity:100.00 (214 nm), 100.00 (254 nm). H NMR (400 MHz, DMSO-d₆) δ 8.03 (s,1H), 7.86 (s, 1H), 7.81 (d, J=8 Hz, 1H), 7.68 (s, 2H), 7.51 (s, 1H),7.47 (d, J=8 Hz, 1H), 6.95 (d, J=7.2 Hz, 1H), 6.52 (d, J=7.2 Hz, 1H),4.82 (d, J=5.6 Hz, 2H), 4.46 (s, 2H), 1.90-1.87 (m, 1H), 0.98-0.91 (m,2H), 0.69-0.65 (m, 2H)

Example 178

Synthesis of 4-cyclopropylpyridin-2-amine

A mixture of 4-bromopyridin-2-amine (5 g, 28.9 mmol), cyclopropylboronicacid (3.2 g, 37.6 mmol), Pd(OAc)₂ (325 mg, 1.45 mmol), SPhos (948 mg,2.31 mmol) and K₃PO₄ (12.3 g, 57.8 mmol) in toluene (80 mL) and H₂O (10mL) was stirred at 90° C. under nitrogen atmosphere overnight. Thereaction mixture was cooled to RT, filtered and concentrated to get thecrude product which was purified by flash column chromatography (0-60%EtOAc in Petroleum ether) to get 4-cyclopropylpyridin-2-amine (750 mg,19%) as a yellow solid. ESI-MS [M+H]⁺: 135.1.

Synthesis of 4-cyclopropyl-2-iminopyridin-1(2H)-amine2,4,6-trimethylbenzenesulfonate

To a solution of 4-cyclopropylpyridin-2-amine (536 mg, 4 mmol) in DCM(10 mL) was added a solution of O-(mesitylsulfonyl)hydroxylamine (2.58g, 12 mmol) in DCM (10 mL). The resulting mixture was stirred at RTovernight and concentrated to get the crude product4-cyclopropyl-2-iminopyridin-1(2H)-amine 2,4,6-trimethylbenzenesulfonate(3.12 g) which was used into next step directly without purification.

Synthesis of2-(chloromethyl)-7-cyclopropyl-[1,2,4]triazolo[1,5-a]pyridine

A mixture of 4-cyclopropyl-2-iminopyridin-1(2H)-amine2,4,6-trimethylbenzenesulfonate (3.12 g, crude), methyl 2-chloroacetate(1.3 g, 12 mmol) and K₂CO₃ (1.66 g, 12 mmol) in EtOH (15 mL) was stirredat 80° C. overnight. The reaction mixture was concentrated. The residuewas partitioned between DCM (20 mL) and H₂O (20 mL). The layers wereseparated and the aqueous phase was extracted with DCM (2×30 mL). Thecombined organic layers were washed with brine (10 mL), dried overNa₂SO₄, filtered and concentrated to get the crude product which waspurified by column chromatography (PE/EtOAc=10/1-3/1) to get2-(chloromethyl)-7-cyclopropyl-[1,2,4]triazolo[1,5-a]pyridine (230 mg,28% over 2 steps) as a light yellow solid. ESI-MS [M+H]⁺: 208.0.

Synthesis of2-(azidomethyl)-7-cyclopropyl-[1,2,4]triazolo[1,5-a]pyridine

To a solution of2-(chloromethyl)-7-cyclopropyl-[1,2,4]triazolo[1,5-a]pyridine (230 mg,1.1 mmol) in DMF (5 mL) was added sodium azide (145 mg, 2.2 mmol). Theresulting mixture was stirred at RT overnight. The reaction mixture wasconcentrated. The residue was partitioned between DCM (30 mL) and H₂O(20 mL). The layers were separated and the aqueous phase was extractedwith DCM (2×30 mL). The combined organic phase was washed with brine (10mL), dried over Na₂SO₄, filtered and concentrated to get2-(azidomethyl)-7-cyclopropyl-[1,2,4]triazolo[1,5-a]pyridine (185 mg,77.8%) as a light yellow solid. The crude product was used into nextstep directly. ESI-MS [M+H]⁺: 215.1.

Synthesis of Ethyl1-((7-cyclopropyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate

To a solution of2-(azidomethyl)-7-cyclopropyl-[1,2,4]triazolo[1,5-a]pyridine (180 mg,0.84 mmol) in t-BuOH (2 mL) and H₂O (2 mL) was added sequentially ofCuSO4.5H₂O (42 mg, 0.17 mmol), sodium ascorbate (51 mg, 0.25 mmol) andethyl propiolate (165 mg, 1.68 mmol). The resulting mixture was stirredat RT for 3 h. The reaction mixture was concentrated to get the crudeproduct which was purified by flash column chromatography (0-8% MeOH inDCM) to get ethyl1-((7-cyclopropyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(155 mg, yield: 59%) as a dark yellow solid. ESI-MS [M+H]⁺: 312.9. ¹HNMR (400 MHz, MeOD) δ 7.80 (s, 1H), 7.69 (d, J=7.2 Hz, 1H), 6.52 (s,1H), 6.03 (d, J=7.2 Hz, 1H), 5.05 (s, 2H), 3.99 (s, 3H), 3.51 (q, J=7.1Hz, 2H), 1.28-1.16 (m, 1H), 0.50 (t, J=7.1 Hz, 3H), 0.32-0.22 (m, 2H),0.06-0.01 (m, 2H).

Synthesis of1-((7-cyclopropyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicAcid

To a solution of ethyl1-((7-cyclopropyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(205 mg, 0.66 mmol) in THF (6 mL) and MeOH (6 mL) was added a solutionof NaOH (78 mg, 1.97 mmol) in H₂O (6 mL). The mixture was stirred at RTfor 3 h. The volatile was removed in vacuo and the aqueous phase wasacidified to pH 4-5 with 2N HCl. The precipitate formed was collected byfiltration and washed with H₂O, lyophilized to get1-((7-cyclopropyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (145 mg, 78%) as a pale yellow solid. ESI-MS [M+H]⁺: 285.0.

Synthesis ofN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((7-cyclopropyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(I-178)

To a mixture of1-((7-cyclopropyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (70 mg, 0.25 mmol), HATU (105 mg, 0.27 mmol) and DIPEA (97 mg, 0.75mmol) in DMF (5 mL) was added(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride(61 mg, 0.26 mmol). The resulting mixture was stirred at RT for 1 h. Thereaction mixture was concentrated. The residue was partitioned betweenDCM (10 mL) and H₂O (10 mL). The layers were separated and the aqueousphase was extracted with DCM (2×10 mL). The combined organic phase waswashed with brine (10 mL), dried over Na₂SO₄, filtered and concentrated.The crude product was purified by flash column chromatography (0-10%MeOH in DCM) to getN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((7-cyclopropyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(70 mg, 61%) as a white solid. ESI-MS [M+H]⁺: 465.8. Purity: 100.00 (214nm), 100.00 (254 nm). ¹H NMR (400 MHz, CDCl₃) δ 8.36 (d, J=7.1 Hz, 1H),8.32 (s, 1H), 8.21 (s, 1H), 7.77-7.66 (m, 2H), 7.34 (s, 1H), 6.74 (d,J=7.1 Hz, 1H), 6.54 (t, J=6.7 Hz, 1H), 5.81 (s, 2H), 4.97 (d, J=5.0 Hz,2H), 2.07-1.96 (m, 1H), 1.20-1.09 (m, 2H), 0.89-0.77 (m, 2H).

Example 179

Synthesis of tert-butyl1-((8-((tert-butoxycarbonyl)amino)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate

To a solution of tert-butyl1-((8-bromo-6-cyclopropylimidazo[1,2-a]365yridine-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(1 g, 2 mmol) and tert-butyl carbamate (0.56 g, 4 mmol) in dioxane (10mL) was added Pd₂(dba)₃ (0.18 g, 0.2 mmol), XantPhos (0.23, 0.4 mmol),Cs₂CO₃ (1.95 g, 6 mmol). The reaction mixture was stirred at 100° C. for16 h under N2. The reaction mixture was cooled to RT and H₂O (50 mL) wasadded. The aqueous phase was extracted with ethyl acetate (100 mL×3),the combined organic layers were dried over sodium sulfate, evaporatedand the residue was purified by silica gel chromatography(DCM:MeOH=15:1) to give the tert-butyl1-((8-((tert-butoxycarbonyl)amino)-6-cyclopropylimidazo[1,2-a]365yridine-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(900 mg, 99%) as a yellow solids. ESI-MS [M+H]⁺: 455.2.

Synthesis of Methyl1-((8-amino-6-cyclopropylimidazo[1,2-a]365yridine-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate

A solution of tert-butyl1-((8-((tert-butoxycarbonyl)amino)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(300 mg, 0.66 mmol) in MeOH (5 mL) and HCl in dioxane (4 M, 5 mL) wasstirred at RT for 16 h. LCMS showed the reaction was complete. Thesolvent of the reaction mixture was evaporated to give the crude productwhich was used in next step without further purification. (230 mg, yield100%) as a yellow solids. ESI-MS [M+H]⁺: 313.3.

Synthesis of Methyl1-((6-cyclopropyl-8-(1H-tetrazol-1-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate

A solution of methyl1-((8-amino-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(230 mg, 0.74 mmol) in trimethoxymethane (4 mL) was added NaN₃ (192 mg,2.96 mmol) at 0° C. The mixture was stirred at 0° C. for 0.5 h. ThenHOAc (4 mL) was added, the mixture was stirred at 50° C. for 16 h, sat.NaHCO₃ (aq) was added to PH about 8, extracted with EtOAc (100 mL×3),The combined organic layers were washed with brine (50 mL×2), dried overanhydrous sodium sulfate and concentrated to give the crude product,which was purified by silica gel chromatography (DCM:MeOH=15:1) to givemethyl1-((6-cyclopropyl-8-(1H-tetrazol-1-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(130 mg, yield: 48%) as a yellow solid. ESI-MS [M+H]⁺: 366.3.

Synthesis of1-((6-cyclopropyl-8-(1H-tetrazol-1-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicAcid

To a solution of methyl1-((6-cyclopropyl-8-(1H-tetrazol-1-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(130 mg, 0.35 mmol) in MeOH (5 mL) and H₂O (5 mL) was added LiOH.H₂O(59.8 mg, 1.42 mmol) and the reaction mixture was stirred at 50° C. for2 h. Most of the solvent was removed and the residue was diluted withH₂O (10 mL), the pH value of mixture was adjusted to 4-5 by adding HClaqueous (1 M). The precipitate was collected and dried to give1-((6-cyclopropyl-8-(1H-tetrazol-1-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (93 mg yield 75%) as a white solids. ESI-MS [M+H]⁺: 352.1.

Synthesis ofN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(1H-tetrazol-1-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(I-179)

To a solution of1-((6-cyclopropyl-8-(H-tetrazol-1-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (40 mg, 0.113 mmol) in dry DMF (3 mL), was added(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride(40 mg, 0.17 mmol), HATU (51 mg, 0.136 mmol) and DIPEA (58 mg, 0.45mmol), the reaction mixture was stirred at RT for 5 h. The reactionmixture diluted with H₂O (20 mL), extracted with ethyl acetate (30mL×3). The combined organic layers were washed with brine (20 mL×2),dried over anhydrous sodium sulfate and concentrated in vacuo. Theresidue was purified by Prep-TLC (DCM/MeOH=10:1) to affordN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(1H-tetrazol-1-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(33 mg, yield: 55%) as a white solids. ESI-MS [M+H]⁺: 533.20. Purity:96.16 (214 nm), 97.18 (254 nm). ¹H NMR (400 MHz, DMSO-d₆) δ 10.29 (s,1H), 8.71 (m, 2H), 8.63 (s, 1H), 8.46 (d, J=1.7 Hz, 1H), 8.23 (d, J=7.3Hz, 1H), 8.10 (s, 1H), 7.74 (s, 1H), 6.76 (t, J=6.9 Hz, 1H), 5.82 (s,2H), 4.70 (d, J=5.3 Hz, 2H), 2.14-2.04 (m, 1H), 1.00 (m, 2H), 0.79 (m,2H).

Example 180

Synthesis of Methyl1-((6-cyclopropyl-1-4H-1,2,4-triazol-4-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate

To a mixture of methyl1-((8-amino-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(240 mg, 0.77 mmol), N′-formylformohydrazide (203 mg, 2.3 mmol) andtriethylamine (0.74 mL, 5.39 mmol) in pyridine (5 mL) was addedchlorotrimethylsilane (1.25 g, 11.55 mmol) drop-wise and the resultingsolution was stirred for 16 h at 100° C., then cooled to RT. Theresulting mixture was concentrated and the residue was diluted with H₂O(20 mL), extracted with ethyl acetate (3×50 mL). the combined organiclayers were washed with brine (50 mL), dried (MgSO₄), and concentratedunder reduced pressure. The crude residue was purified by silica gelcolumn chromatography (Dichloromethane:Methanol=10:1) to give the methyl1-((6-cyclopropyl-8-(4H-1,2,4-triazol-4-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(150 mg, yield 54%) as a white solid. ESI-MS [M+H]⁺: 365.4.

Synthesis of1-((6-cyclopropyl-8-(4H-1,2,4-triazol-4-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicAcid

To a solution of methyl1-((6-cyclopropyl-8-(4H-1,2,4-triazol-4-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(145 mg, 0.398 mmol) in MeOH (5 mL) and H₂O (5 mL) was added LiOH.H₂O(66 mg, 1.589 mmol) and the reaction mixture was stirred at 50° C. for 3h. Most of the solvent was removed and the residue was diluted with H₂O(10 mL), the pH value of mixture was adjusted to 4 by adding HCl aqueous(1 M). The precipitate was collected and dried to give the1-((6-cyclopropyl-8-(4H-1,2,4-triazol-4-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (120 mg, yield 87%) as a white solids. ESI-MS [M+H]⁺: 351.1

Synthesis ofN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(4H-1,2,4-triazol-4-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(I-180)

To a solution of1-((6-cyclopropyl-8-(4H-1,2,4-triazol-4-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (120 mg, 0.34 mmol) in dry DMF (3 mL) was added(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride(96 mg, 0.41 mmol), HATU (155.8 mg, 0.41 mmol) and DIPEA (175 mg, 1.36mmol), the reaction mixture was stirred at RT for 2 h. The reactionmixture diluted with H₂O (20 mL), extracted with ethyl acetate (30mL×3). The combined organic layers were washed with brine (20 mL×2),dried over anhydrous sodium sulfate and concentrated in vacuo. Theresidue was purified by Prep-TLC (DCM/MeOH=10:1) to affordN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(4H-1,2,4-triazol-4-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(50 mg, yield: 28%) as a white solid. ESI-MS [M+H]⁺: 532.20. Purity:98.96 (214 nm), 99.41 (254 nm). ¹H NMR (400 MHz, DMSO-d₆) δ 9.40 (s,2H), 8.71 (t, J=5.4 Hz, 1H), 8.64 (s, 1H), 8.47 (d, J=1.0 Hz, 1H), 8.44(d, J=2.4 Hz, 1H), 8.20 (d, J=7.4 Hz, 1H), 8.01 (s, 1H), 7.46 (d, J=1.3Hz, 1H), 6.79-6.71 (m, 1H), 5.81 (s, 2H), 4.70 (d, J=5.5 Hz, 2H),2.04-1.95 (m, 1H), 1.02-0.94 (m, 2H), 0.86-0.79 (m, 2H).

Example 181

Synthesis ofN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(hydroxymethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(I-181)

To the solution of1-((6-cyclopropyl-8-(hydroxymethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (300 mg, 0.96 mmol) and(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride(338 mg, 1.44 mmol) in dry DMF (5 mL) was added HOBT (156 mg, 1.15mmol), EDCI (221 mg, 1.15 mmol) and DIPEA (371 mg, 2.88 mmol) at RT. Thereaction mixture was stirred at RT for 18 h and then poured into H₂O (20mL). The precipitate was filtered and washed with H₂O (10) and hexane(20). The solid was dried to affordedN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(hydroxymethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(410 mg, yield: 86%) as a white solid. ESI-MS [M+H]⁺: 495.1. Purity:95.21 (214 nm), 97.34 (254 nm). ¹H NMR (400 MHz, DMSO-d₆) δ 8.71 (t,J=5.4 Hz, 1H), 8.54 (s, 1H), 8.44 (d, J=2.3 Hz, 1H), 8.26-8.17 (m, 2H),7.81 (s, 1H), 7.01 (d, J=1.3 Hz, 1H), 6.80-6.72 (m, 1H), 5.72 (s, 2H),5.33 (t, J=5.7 Hz, 1H), 4.74 (d, J=5.6 Hz, 2H), 4.70 (d, J=5.5 Hz, 2H),1.98-1.90 (m, 1H), 0.96-0.89 (m, 2H), 0.69-0.62 (m, 2H).

Example 182

Synthesis ofN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-formylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(I-182)

To the mixture ofN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(hydroxymethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(300 mg, 0.61 mmol) in DCM/DMF (15 mL/15 mL) was added DMP (515 mg, 1.21mmol) at RT. The reaction mixture was stirred at RT for 3 h and thenquenched with sat. NaHCO₃ (30 mL). The mixture was extracted with DCM(30 mL*3). The combined organic layer was washed with saturated salt H₂Oand concentrated. The residue was purified by flash columnchromatography to affordedN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-formylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(130 mg, yield: 43%) as a brown solid and of which 50 mg target compoundwas further purified by prep-HPLC to give a light yellow solid (8.5 mg,yield: 17%). ESI-MS [M+H]⁺: 493.1. Purity: 100% (214 nm), 100% (254 nm).¹H NMR (400 MHz, DMSO-d₆) δ 10.44 (s, 1H), 8.75-8.68 (m, 2H), 8.58 (s,1H), 8.44 (d, J=2.4 Hz, 1H), 8.20 (d, J=7.4 Hz, 1H), 7.97 (s, 1H), 7.61(d, J=1.7 Hz, 1H), 6.80-6.72 m, 1H), 5.82 (s, 2H), 4.70 (d, J=5.5 Hz,2H), 2.10-2.00 (m, 1H), 1.01-0.95 (m, 2H), 0.77-0.71 (m, 2H).

Example 183

Synthesis of1-((8-(3-amino-3-oxopropyl)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(I-183)

To a solution of3-(2-((4-(((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)propanoicacid (145 mg, 0.28 mmol) in DMF (5 mL) was added EDCI (110 mg, 0.58mmol), HOBT (78 mg, 0.58 mmol), DIPEA (195 mg, 1.5 mmol) and NH₄Cl (30mg, 0.55 mmol) at RT. The mixture was stirred for 14 h. The mixture wasconcentrated and purified by Prep-HPLC to1-((8-(3-amino-3-oxopropyl)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(5 mg, yield: 3.5%) as a white solid. ESI-MS [M+H]⁺: 518.1. Purity:97.17% (214 nm), 96.33% (254 nm). ¹H NMR (400 MHz, DMSO-d₆) δ 8.92 (t,J=5.9 Hz, 1H), 8.57 (s, 1H), 8.34-8.28 (m, 2H), 8.19 (d, J=1.0 Hz, 1H),7.89-7.82 (m, 1H), 7.77 (s, 1H), 7.30 (s, 1H), 6.85-6.75 (m, 2H), 6.65(dd, J=7.5, 2.1 Hz, 1H), 5.73 (s, 2H), 4.62 (d, J=5.9 Hz, 2H), 3.02 (t,J=7.6 Hz, 2H), 2.49-2.46 (m, 2H) 1.92-1.82 (m, 1H), 0.95-0.84 (m, 2H),0.70-0.59 (m, 2H).

Example 184

Synthesis ofN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((8-(2-cyanoethyl)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(I-184)

A solution of1-((8-(3-amino-3-oxopropyl)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(100 mg, 0.19 mmol) in POCl₃ (2 mL) was heated to 60° C. and stirred for5 h. The mixture was concentrated and purified by prep-HPLC to giveN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((8-(2-cyanoethyl)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(8.2 mg, yield: 8.6%) as a white solid. ESI-MS [M+H]⁺: 500.2. Purity:98.62% (214 nm), 98.42% (254 nm). ¹H NMR (400 MHz, DMSO-d₆) δ 8.92 (t,J=5.9 Hz, 1H), 8.57 (s, 1H), 8.38-8.21 (m, 3H), 7.86-7.80 (m, 2H), 6.96(s, 1H), 6.64 (dd, J=7.5, 2.1 Hz, 1H), 5.74 (s, 2H), 4.61 (d, J=5.9 Hz,2H), 3.11 (t, J=7.1 Hz, 2H), 3.00 (t, J=6.8 Hz, 2H), 1.96-1.86 (m, 1H),0.96-0.88 (m, 2H), 0.71-0.63 (m, 2H).

Example 185

Synthesis of2-(chloromethyl)-6-cyclopropyl-8-(trifluoromethyl)imidazo[1,2-a]pyridine

A mixture of 5-cyclopropyl-3-(trifluoromethyl)pyridin-2-amine (600 mg, 3mmol) and 1,3-dichloropropan-2-one (1.14 g, 9 mmol) in EtOH (5 mL) wasstirred at 85° C. overnight. The mixture was concentrated, saturatedaqueous NaHCO₃ was added to adjust pH to about 8, then extracted withEtOAc (50 mL*2), the combined organic layers were dried over Na₂SO₄,concentrated and purified by silica gel chromatography (PE/EA=2/1) togive2-(chloromethyl)-6-cyclopropyl-8-(trifluoromethyl)imidazo[1,2-a]pyridine(350 mg, yield: 43%) as a brown solid. ESI-MS [M+H]⁺: 275.1.

Synthesis of2-(azidomethyl)-6-cyclopropyl-8-(trifluoromethyl)imidazo[1,2-a]pyridine

A mixture of2-(chloromethyl)-6-cyclopropyl-8-(trifluoromethyl)imidazo[1,2-a]pyridine(43 mg, 0.16 mmol) and NaN₃ (13 mg, 0.19 mmol) in DMF (2 mL) was stirredat RT for 3 h. Water (20 mL) was added and extracted with EtOAc (30mL*3). The combined organic layers were washed by brine (20 mL*2), driedover Na₂SO₄, concentrated to give2-(azidomethyl)-6-cyclopropyl-8-(trifluoromethyl)imidazo[1,2-a]pyridine(40 mg, yield: 89%) as a yellow solid. ESI-MS [M+H]⁺: 282.1

Synthesis of Ethyl1-((6-cyclopropyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate

A mixture of2-(azidomethyl)-6-cyclopropyl-8-(trifluoromethyl)imidazo[1,2-a]pyridine(80 mg, 0.28 mmol), ethyl propiolate (84 mg, 0.85 mmol), CuSO₄ (23 mg,0.14 mmol) and sodium ascorbate (25 mg, 0.14 mmol) in H₂O/i-PrOH (2 mL/2mL) was stirred at RT for 3 h. Water (20 mL) was added and extractedwith EtOAc (30 mL*3). The combined organic layers were washed by brine(20 mL), dried over Na₂SO₄, concentrated and purified by silica gelchromatography (CH₂Cl₂/MeOH=15/1) to give ethyl1-((6-cyclopropyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(40 mg, yield: 38%) as a yellow solid. ESI-MS [M+H]⁺: 380.1.

Synthesis of1-((6-cyclopropyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicAcid

A mixture of ethyl1-((6-cyclopropyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(350 mg, 0.9 mmol) and LiOH.H₂O (76 mg, 1.8 mmol) in THF/EtOH/H₂O (4mL/4 mL/2 mL) was stirred at 50 C for 3 h. Most of the solvent wasremoved and the residue was diluted with H₂O (5 mL), the pH value ofmixture was adjusted to 4-5 by adding HCl aqueous (1 M). The precipitatewas collected and dried to give1-((6-cyclopropyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (300 mg, yield: 95%) as a white solid. ESI-MS [M+H]⁺: 352.1.

Synthesis ofN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(I-185)

A mixture of1-((6-cyclopropyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (40 mg, 0.11 mmol),(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride(26 mg, 0.11 mmol), HOBT (30 mg, 0.22 mmol), EDCI (43 mg, 0.22 mmol) andDIPEA (71 mg, 0.55 mmol) in DMF (3 mL) was stirred at RT for 16 h. Thereaction mixture was poured into H₂O, the precipitated was filtrated andwashed with CH₃OH to to giveN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(38 mg, yield: 65%) as a white solid. ESI-MS [M+H]⁺: 533.1. Purity:99.13 (214 nm), 97.09 (254 nm). ¹H NMR (400 MHz, DMSO-d₆) δ 8.72 (t,J=5.4 Hz, 1H), 8.61 (s, 1H), 8.57 (s, 1H), 8.44 (d, J=2.4 Hz, 1H), 8.20(d, J=7.4 Hz, 1H), 7.93 (s, 1H), 7.51 (s, 1H), 6.77-6.74 (m, 1H), 5.81(s, 2H), 4.70 (d, J=5.5 Hz, 2H), 2.06-1.99 (m, 1H), 0.98-093 (m, 2H),0.77-0.73 (m, 2H).

Example 186

Synthesis of Ethyl1-((6-cyclopropyl-8-(hydroxymethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate

To a solution of1-((6-cyclopropyl-8-(hydroxymethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (800 mg, 2.56 mmol) in EtOH (50 mL) was added SOCl₂ (10 mL). Theresulting reaction was stirred at 70° C. for 14 h. The reaction wasconcentrated in vacuo to give the ethyl1-((6-cyclopropyl-8-(hydroxymethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylateas a yellow solid. (850 mg, 97.5%). ESI-MS[M+H]⁺: 342.2

Synthesis of Ethyl1-((8-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate

To a solution of ethyl1-((6-cyclopropyl-8-(hydroxymethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(850 mg, 2.49 mmol) in DCM (25 mL) was added SOCl2 (3 mL) at 0° C. Theresulting reaction was stirred at RT for 4 h. The reaction wasconcentrated in vacuo to give the ethyl1-((8-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylateas a yellow solid (900 mg crude). ESI-MS [M+H]⁺: 360.3

Synthesis of Ethyl1-((6-cyclopropyl-8-((triphenyl-4-phosphanyl)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate

A mixture of ethyl1-((8-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(900 mg crude form previous step) and PPh3 (720 mg, 2.74 mmol) intoluene (40 mL) was stirred at 110° C. for 12 h. The reaction wasconcentrated in vacuo to give the ethyl1-((6-cyclopropyl-8-((triphenyl-14-phosphanyl)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylateas a yellow solid, which was used into next step without furtherpurification (1.62 g crude). ESI-MS [M+H]⁺: 586.1.

Synthesis of Ethyl1-((6-cyclopropyl-8-(oxetan-3-ylidenemethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate

A mixture of ethyl1-((6-cyclopropyl-8-((triphenyl-14-phosphanyl)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(1 g crude from previous step), oxetan-3-one (369 mg, 5.1 mmol) and NaH(340 mg, 8.5 mmol, 60 wt % in oil) in THF (30 mL) was stirred at 65° C.for 14 h under N₂. The reaction was quenched with aqueous NH₄Cl (50 mL),extracted with EtOAc (50 mL×3). The combined organic layers were washedwith brine, dried over Na₂SO₄, concentrated in vacuo to give the crudeproduct, which was purified with silica gel (eluent: DCM/MeOH=30/1) togive the ethyl1-((6-cyclopropyl-8-(oxetan-3-ylidenemethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylateas a yellow solid. (450 mg, 47.7% over 3 steps). ESI-MS [M+H]⁺: 380.2.

Synthesis of Ethyl1-((6-cyclopropyl-8-(oxetan-3-ylmethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate

A mixture of ethyl1-((6-cyclopropyl-8-(oxetan-3-ylidenemethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(450 mg, 1.19 mmol) and Pd/C (100 mg) in THF (25 mL) was stirred underH₂ atmosphere for 2 h. The reaction was filtered and concentrated invacuo to give the ethyl1-((6-cyclopropyl-8-(oxetan-3-ylmethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylateas a yellow solid (180 mg, 40%). ESI-MS [M+H]⁺: 382.2

Synthesis of1-((6-cyclopropyl-8-(oxetan-3-ylmethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicAcid

To a solution of ethyl1-((6-cyclopropyl-8-(oxetan-3-ylmethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(180 mg, 0.47 mmol) in THF/H₂O (8 mL/8 mL) was added LiOH.H₂O (79 mg,1.88 mmol). The resulting mixture was stirred at RT for 4 h. Thereaction was concentrated in vacuo to give the crude product, which waspurified with Prep-HPLC to give1-((6-cyclopropyl-8-(oxetan-3-ylmethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid as a white solid (90 mg, 54%). ESI-MS [M+H]⁺: 354.2

Synthesis ofN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(oxetan-3-ylmethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(I-186)

To a solution of1-((6-cyclopropyl-8-(oxetan-3-ylmethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (40 mg, 0.11 mmol),(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride(33 mg, 0.14 mmol), HATU (78 mg, 0.2 mmol) in DMF (6 mL) was added DIPEA(71 mg, 0.55 mmol). The resulting reaction was stirred at RT for 14 h.The reaction was poured into H₂O (30 mL) and white solid was formed. Thesolid was filtered and washed with MeOH (30 mL) to give theN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(oxetan-3-ylmethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamideas a white solid. (20 mg, 34%). ESI-MS [M+H]⁺: 535.2. Purity: 89.80%(214 nm), 93.09 (254 nm). ¹H NMR (400 MHz, DMSO-d₆) δ 8.72-8.65 (m, 1H),8.54 (s, 1H), 8.44 (d, J=2.4 Hz, 1H), 8.21-8.20 (m, 2H), 7.78 (s, 1H),6.80 (s, 1H), 6.78-6.74 (m, 1H), 5.73 (s, 2H), 4.70 (d, J=4.0 Hz, 2H),4.62-4.59 (m, 2H), 4.36 (t, J=6.0 Hz, 2H), 3.42-3.39 (m, 1H), 3.16 (d,J=7.7 Hz, 2H), 1.91-1.85 (m, 1H), 0.92-0.88 (m, 2H), 0.68-0.64 (m, 2H).

Example 187

Synthesis of 3-(2-amino-5-chloropyridin-3-yl)oxetan-3-ol

To a solution of 3-bromo-5-chloropyridin-2-amine (2 g, 9.7 mmol) in THF(100 mL) was added n-BuLi (5.3 mL, 12.5 mmol, 2.4 M in hexane) slowly at−78° C. The reaction was stirred at −78° C. for another 20 min. Thenoxetan-3-one (1.4 g, 19.4 mmol) in THF (20 mL) was added thereto. Thereaction was stirred at −78° C. for 1 h. The reaction was quenched withaqueous NH₄Cl (100 mL), extracted with EtOAc (100 mL×3). The combinedorganic layers were washed with brine, dried over Na₂SO₄, concentratedin vacuo to give the crude product, which was purified with silica gel(DCM/MeOH=25/1) to give the 3-(2-amino-5-chloropyridin-3-yl)oxetan-3-olas a yellow solid. (1.5 g, 77%). ESI-MS [M+H]⁺: 201.3.

Synthesis of3-(6-chloro-2-(chloromethyl)imidazo[1,2-a]pyridin-8-yl)oxetan-3-ol

A mixture of 3-(2-amino-5-chloropyridin-3-yl)oxetan-3-ol (1.5 g, 7.5mmol) and 1,3-dichloropropan-2-one (2.9 g, 22.5 mmol) in EtOH (50 mL)was stirred at 95° C. for 14 h. The reaction was concentrated in vacuoto remove the EtOH. The pH of residue was adjusted to 9 by saturatedaqueous NaHCO₃, extracted with EtOAc (100 mL×3). The combined organiclayers were washed with brine, dried over Na₂SO₄, concentrated in vacuoto give the3-(6-chloro-2-(chloromethyl)imidazo[1,2-a]pyridin-8-yl)oxetan-3-ol as abrown solid. (1.1 g, 53.7%). ESI-MS [M+H]⁺: 273.2.

Synthesis of3-(2-(azidomethyl)-6-chloroimidazo[1,2-a]pyridin-8-yl)oxetan-3-ol

A mixture of (1.1 g, 4.04 mmol) and NaN₃ (342 mg, 5.26 mmol) in DMF (30mL) was stirred at RT for 2 h. H₂O (50 mL) was added to the reaction,extracted with EtOAc (100 mL×3). The combined organic layers were washedwith brine, dried over Na₂SO₄, concentrated in vacuo to give the3-(2-(azidomethyl)-6-chloroimidazo[1,2-a]pyridin-8-yl)oxetan-3-ol asyellow oil, which was used into next step without further purification(1.2 g crude). ESI-MS [M+H]⁺: 280.2

Synthesis of Ethyl1-((6-chloro-8-(3-hydroxyoxetan-3-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate

To a solution of3-(2-(azidomethyl)-6-chloroimidazo[1,2-a]pyridin-8-yl)oxetan-3-ol (1.2 gcrude from previous step) and ethyl propiolate (475 mg, 4.85 mmol) int-BuOH/H₂O (20 mL/20 mL) was added CuSO₄ (64 mg, 0.41 mmol) and sodiumascorbate (81 mg, 0.41 mmol). The resulting mixture was stirred at RTfor 2 h. H₂O (50 mL) was added to the reaction, extracted with EtOAc(100 mL×3). The combined organic layers were washed with brine, driedover Na₂SO₄, concentrated in vacuo to give the crude product, which waspurified with silica gel (DCM/MeOH=40/1) to give the ethyl1-((6-chloro-8-(3-hydroxyoxetan-3-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylateas a yellow solid (500 mg, 32.9% over 2 step). ESI-MS [M+H]⁺: 378.2

Synthesis of Ethyl1-((6-chloro-8-(3-(((methylthio)carbonothioyl)oxy)oxetan-3-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate

To a solution of ethyl1-((6-chloro-8-(3-hydroxyoxetan-3-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(500 mg, 1.33 mmol) in THF (20 mL) was added NaH (266 mg, 6.65 mmol, 60wt % in oil). After stirring at 0° C. for 30 min, a solution of CS₂ (505mg, 6.65 mmol) in THF (5 mL) was added and stirred at 0° C. for another30 min. A solution MeI (944 mg, 6.65 mmol) in THF (4 mL) was added, theresulting reaction was stirred at 0° C. for another 1 h. The reactionwas quenched with aqueous NH₄Cl (50 mL), extracted with EtOAc (100mL×3). The combined organic layers were washed with brine, dried overNa₂SO₄, concentrated in vacuo to give the ethyl1-((6-chloro-8-(3-(((methylthio)carbonothioyl)oxy)oxetan-3-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylateas a yellow solid, which was used into next step without furtherpurification (650 mg crude). ESI-MS [M+H]⁺: 468.2.

Synthesis of Ethyl1-((6-chloro-8-(oxetan-3-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate

A mixture of ethyl1-((6-chloro-8-(3-(((methylthio)carbonothioyl)oxy)oxetan-3-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(650 mg crude from previous step), Tributyltin (582 mg, 2 mmol) and AIBN(328 mg, 2 mmol) in toluene (20 mL) was stirred at 125° C. for 1 h. Thereaction was concentrated in vacuo to give the crude product, which waspurified with silica gel (DCM/MeOH=30/1) to give the ethyl1-((6-chloro-8-(oxetan-3-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylateas a yellow solid (300 mg, 62.5%). ESI-MS [M+H]⁺: 362.2.

Synthesis of1-((6-chloro-8-(oxetan-3-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicAcid

To a solution of ethyl1-((6-chloro-8-(oxetan-3-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(300 mg, 0.83 mmol) in THF/H₂O (15 mL/15 mL) was added LiOH.H₂O (105 mg,2.5 mmol). The resulting reaction was stirred at RT for 3 h. Thereaction was concentrated in vacuo to give the crude product, which waspurified with Prep-HPLC to give the1-((6-chloro-8-(oxetan-3-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid as a white solid (180 mg, 65.2%). ESI-MS [M+H]⁺: 334.2

Synthesis of1-((6-chloro-8-(oxetan-3-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(I-187)

To a solution1-((6-chloro-8-(oxetan-3-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (80 mg, 0.24 mmol),(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride(73 mg, 0.31 mmol) and HATU (148 mg, 0.39 mmol) in DMF (10 mL) was addedDIPEA (155 mg, 1.2 mmol). The resulting reaction was stirred at RT for12 h. The reaction was poured into H₂O (50 mL) and the white solid wasformed. The solid was filtered and washed with MeOH (50 mL) to give the1-((6-chloro-8-(oxetan-3-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-1,2,3-triazole-4-carboxamideas a white solid. (50 mg, 40.6%). ESI-MS [M+H]⁺: 515.2. Purity: 94.23(214 nm), 96.17 (254 nm). ¹H NMR (400 MHz, DMSO-d₆) δ 8.74-8.73 (m, 2H),8.56 (s, 1H), 8.44 (s, 1H), 8.21 (d, J=7.0 Hz, 1H), 7.90 (s, 1H), 7.38(s, 1H), 6.76 (t, J=6.1 Hz, 1H), 5.77 (s, 2H), 4.95-4.92 (m, 2H),4.82-4.79 (m, 2H), 4.70-4.69 (m, 3H).

Example 188

Synthesis of 6,7-dichloro-2-(chloromethyl)imidazo[1,2-a]pyridine

The mixture of 4,5-dichloropyridin-2-amine (1 g, 6.13 mmol) and1,3-dichloropropan-2-one (10 g, 78.4 mmol) in DMF (20 mL) was stirred at90° C. for 20 h. Then H₂O (100 mL) was added and extracted with EtOAc(100 mL×2). The combined organic layers were concentrated to give thecrude product which was purified by silica gel chromatography(PE/EtOAc=3/1) to give6,7-dichloro-2-(chloromethyl)imidazo[1,2-a]pyridine (471 mg, yield: 33%)as a yellow solid. ESI-MS [M+H]⁺: 235.1

Synthesis of 2-(azidomethyl)-6,7-dichloroimidazo[1,2-a]pyridine

The reaction mixture of6,7-dichloro-2-(chloromethyl)imidazo[1,2-a]pyridine (823 mg, 3.52 mmol)and NaN₃ (239 mg, 3.68 mmol) in DMF (10 mL) was stirred at RT overnight.Water (100 mL) was added and extracted with EtOAc (100 mL×2). Thecombined organic layers were concentrated to give2-(azidomethyl)-6,7-dichloroimidazo[1,2-a]pyridine (433 mg, yield: 51%)as a yellow solid. This material was used directly in the next stepwithout further purification. ESI-MS [M+H]⁺: 243.1.

Synthesis of Ethyl1-((6,7-dichloroimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate

A mixture 2-(azidomethyl)-6,7-dichloroimidazo[1,2-a]pyridine (433 mg,1.79 mmol), ethyl propiolate (351 mg, 3.58 mmol), CuSO₄ (89 mg, 0.358mmol) and sodium ascorbate (106 mg, 0.537 mmol) in t-BuOH (8 mL) and H₂O(8 mL) was stirred for 2 h at RT. The reaction was concentrated invacuo. Water (20 mL) was added and extracted with EtOAc (50 mL×3). Thecombined organic layers were dried over Na₂SO₄, and concentrated to givethe crude product which was purified by silica gel chromatography(PE/EtOAc=1/1) to give ethyl1-((6,7-dichloroimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(509 mg, yield: 82%) as a yellow solid. ESI-MS [M+H]⁺: 340.2.

Synthesis of1-((6,7-dichloroimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicAcid

A mixture of ethyl1-((6,7-dichloroimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(100 mg, 0.294 mmol) and LiOH.H₂O (12 mg, 0.294 mmol) in THF/H₂O (4 mL/4mL) was stirred at RT overnight. The reaction was adjusted the pH to 5and concentrated in vacuo to give1-((6,7-dichloroimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (120 mg, crude) as a yellow solid. This material was used directlyin the next step without further purification. ESI-MS [M+Na]⁺: 313.2.

Synthesis ofN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6,7-dichloroimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(I-188)

A mixture of1-((6,7-dichloroimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (120 mg, crude),(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride(80 mg, 0.342 mmol), HATU (217 mg, 0.57 mmol) and DIPEA (184 mg, 1.43mmol) in DMF (5 mL) was stirred for 3 h at RT. Water (30 mL) was addedand extracted with EtOAc (50 mL×3). The combined organic layers weredried over Na₂SO₄, and concentrated to give the crude product which waspurified by prep-HPLC to giveN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6,7-dichloroimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(50 mg, yield: 35% over 2 steps) as a light yellow solid. ESI-MS [M+H]⁺:494.2. Purity: 97.67 (214 nm) 96.17 (254 nm). ¹H NMR (400 MHz, DMSO-d₆)δ 9.06 (s, 1H), 8.75-8.69 (m, 1H), 8.58 (s, 1H), 8.45 (s, 1H), 8.21 (d,J=7.2 Hz, 1H), 7.99 (d, J=12 Hz 2H), 7.96 (s, 1H), 6.77 (t, J=7.0 Hz,1H), 5.79 (s, 2H), 4.71 (d, J=5.4 Hz, 2H).

Example 189

Synthesis of 5-cyclopropylthieno[2,3-b]pyridine

To a solution of 5-bromothieno[2,3-b]pyridine (2 g, 9.34 mmol) indioxane/H₂O (100 mL/100 mL) was added cyclopropylboronic acid (1.605 g,18.7 mmol), Pd(OAc)₂ (210 mg, 0.934 mmol), PCy₃ (524 mg, 1.87 mmol) andK₃PO₄ (5.949 g, 28 mmol). The reaction mixture was stirred at 100° C.for 14 h under nitrogen. The mixture was concentrated in vacuo. Water(100 mL) was added and the mixture was extracted with EtOAc (100 mL×3).The combined organic layers were washed with brine, dried over Na₂SO₄,concentrated to give the crude product, which was purified by silica gelchromatography (PE/EtOAc=30/1) to give the5-cyclopropylthieno[2,3-b]pyridine as a yellow oil (1.067 g, yield:65%). ESI-MS [M+H]⁺: 175.9.

Synthesis of 5-cyclopropylthieno[2,3-b]pyridine-2-carbaldehyde

To a solution 5-cyclopropylthieno[2,3-b]pyridine (1.067 g, 6.09 mmol) indry THF (50 mL) at −78° C. was added LDA (17.2 mL, 1 M, 17.2 mmol)dropwise. The mixture was stirred for 30 min at −78° C. DMF (3 mL) wasadded to the reaction above dropwise. The resulting mixture was stirredovernight. The reaction was quenched with saturated aqueous NH₄Cl (50mL), and extracted with EtOAc (80 mL×3). The combined organic layerswere washed with brine, dried over Na₂SO₄, and concentrated to give thecrude product, which was purified by silica gel chromatography(PE/EtOAc=5/1) to give 5-cyclopropylthieno[2,3-b]pyridine-2-carbaldehyde(871 mg, yield: 70%) as a yellow solid. ESI-MS [M+H]⁺: 203.9.

Synthesis of (5-cyclopropylthieno[2,3-b]pyridin-2-yl)methanol

To a solution of 5-cyclopropylthieno[2,3-b]pyridine-2-carbaldehyde (871mg, 4.29 mmol) in MeOH (30 mL) was added NaBH₄ (243 mg, 6.43 mmol). Thereaction mixture was stirred at RT for 0.5 h. The reaction was quenchedwith H₂O, concentrated in vacuo and extracted with EtOAc (30 mL×3). Thecombined organic layers were washed with brine, dried over Na₂SO₄, andconcentrated to give the crude product, which was purified by silica gelchromatography (PE/EtOAc=1/1) to give(5-cyclopropylthieno[2,3-b]pyridin-2-yl)methanol (778 mg, yield: 88%) asa yellow oil. ESI-MS [M+H]⁺: 206.0.

Synthesis of 2-(chloromethyl)-5-cyclopropylthieno[2,3-b]pyridine

A solution of (5-cyclopropylthieno[2,3-b]pyridin-2-yl)methanol (778 mg,3.79 mmol) in SOCl₂ (20 mL) was stirred at RT for 2 h. The reactionmixture was concentrated to give a residue. Water (40 mL) was added tothe residue, and the pH was adjusted to 9 with NaHCO₃ solution, and thenextracted with EtOAc (40 mL×2). The combined organic layers were washedwith brine, dried over Na₂SO₄, concentrated to give the crude product,which was purified by silica gel chromatography (PE/EtOAc=10/1) to give2-(chloromethyl)-5-cyclopropylthieno[2,3-b]pyridine (823 mg, yield: 97%)as a yellow oil. ESI-MS [M+H]⁺: 224.0.

Synthesis of 2-(azidomethyl)-5-cyclopropylthieno[2,3-b]pyridine

A mixture of 2-(chloromethyl)-5-cyclopropylthieno[2,3-b]pyridine (823mg, 3.68 mmol) and NaN₃ (239 mg, 3.68 mmol) in DMF (20 mL) was stirredat RT for overnight. H₂O (50 mL) was added to the reaction, extractedwith EtOAc (50 mL×3). The combined organic layers were washed withbrine, dried over Na₂SO₄, concentrated in vacuo to give2-(azidomethyl)-5-cyclopropylthieno[2,3-b]pyridine (847 mg, yield: 99%)as a yellow solid. This material was used directly in the next stepwithout further purification. ESI-MS [M+H]⁺: 231.0.

Synthesis of Ethyl1-((5-cyclopropylthieno[2,3-b]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate

A solution 2-(azidomethyl)-5-cyclopropylthieno[2,3-b]pyridine (847 mg,3.68 mmol), ethyl propiolate (722 mg, 7.36 mmol), CuSO₄ (184 mg, 0.74mmol) and sodium ascorbate (219 mg, 1.1 mmol) in t-BuOH (15 mL) and H₂O(15 mL) was stirred at RT for 2 h. The reaction was poured into H₂O (50mL) and extracted with EtOAc (80 mL×3). The combined organic layers werewashed with brine, dried over Na₂SO₄, and concentrated to give the crudeproduct, which was purified by silica gel chromatography (PE/EtOAc=2/1)to give ethyl1-((5-cyclopropylthieno[2,3-b]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(778 mg, yield: 64%) as a yellow solid. ESI-MS [M+H]⁺: 329.1.

Synthesis of1-((5-cyclopropylthieno[2,3-b]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicAcid

A solution of ethyl1-((5-cyclopropylthieno[2,3-b]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(100 mg, 0.306 mmol) and LiOH.H₂O (13 mg, 0.306 mmol) in a mixed solventof THF/H₂O (4 mL/4 mL) was stirred at RT for overnight. The reaction wasconcentrated in vacuo to remove the THF. The pH of residue was adjustedto 5, and concentrated in vacuo to give1-((5-cyclopropylthieno[2,3-b]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (120 mg, crude) as a yellow solid. This material was used directlyin the next step without further purification. ESI-MS [M+Na]⁺: 301.1.

Synthesis ofN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((5-cyclopropylthieno[2,3-b]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(I-189)

A mixture of1-((5-cyclopropylthieno[2,3-b]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (120 mg, crude from last step),(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride(84 mg, 0.356 mmol), HATU (225 mg, 0.593 mmol) and DIPEA (192 mg, 1.48mmol) in DMF (10 mL) was stirred at RT for 3 h. The reaction was pouredinto H₂O (50 mL), and a yellow solid precipitated. The mixture wasfiltered and washed with MeOH (50 mL) and dried in vacuo to giveN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((5-cyclopropylthieno[2,3-b]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(98 mg, yield: 68%) as a light yellow solid. ESI-MS [M+H]⁺: 481.7.Purity: 98.12 (214 nm) 98.50 (254 nm). ¹H NMR (400 MHz, DMSO-d₆) δ8.80-8.72 (m, 1H), 8.68 (s, 1H), 8.44 (s, 1H), 8.39 (s, 1H), 8.20 (d,J=7.2 Hz, 1H), 7.87 (s, 1H), 7.35 (s, 1H), 6.80-6.70 (m, 1H), 5.99 (s,2H), 4.70 (d, J=5.4 Hz, 2H), 2.08-2.02 (m, 1H), 1.02 (d, J=8.3 Hz, 2H),0.77 (d, J=5.2 Hz, 2H).

Example 190

Synthesis of 2-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)acetonitrile

To a solution of 2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine (2g, 9.7 mmol) in MeCN (40 mL) was added TMSCN (1.4 g, 14 mmol). Thereaction mixture was stirred at 60° C. overnight under nitrogen. Thenthe mixture was concentrated in vacuo. Water (20 mL) was added to thereaction, extracted with DCM (50 mL×2). The combined organic layers werewashed with brine, dried over Na₂SO₄, concentrated to give the crudeproduct, which was purified by silica gel chromatography (PE/EtOAc=1/1)to give the 2-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)acetonitrile as ayellow solid (650 mg, yield: 34%). ESI-MS [M+H]⁺: 198.1.

Synthesis of Ethyl2-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)-N-hydroxyacetimidamide

To a solution 2-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)acetonitrile(400 mg, 2 mmol) and NH₂OH.HCl (352 mg, 5 mmol) in EtOH (20 mL) wasadded DIPEA (645 mg, 5 mmol). The resulting mixture was stirred at 80°C. overnight under nitrogen. The mixture was concentrated under vacuum.The residue was poured into H₂O (20 mL) and extracted with EtOAc (50mL×2). The combined organic layers were washed with brine, dried overNa₂SO₄, and concentrated to give the crude product, which was purifiedby silica gel chromatography (PE/EA=2/1) to give2-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)-N-hydroxyacetimidamide (340mg, 73%) as a yellow solid. ESI-MS [M+H]⁺: 231.1

Synthesis of Methyl3-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1,2,4-oxadiazole-5-carboxylate

A mixture of2-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)-N-hydroxyacetimidamide (340mg, 1.4 mmol), K₂CO₃ (408 mg, 3 mmol) and methyl 2-chloro-2-oxoacetate(180 mg) in DCM (15 mL) was stirred at 80° C. overnight. Water (5 mL)was added to the reaction, extracted with DCM (40 mL×2). The combinedorganic layers were washed with brine, dried over Na₂SO₄, concentratedto give the crude product, which was purified by silica gelchromatography (PE/EA=2/1) to give methyl3-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1,2,4-oxadiazole-5-carboxylate(100 mg, yield: 22.7%) as a yellow solid. ESI-MS [M+H]⁺: 299.2.

Synthesis ofN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-3-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1,2,4-oxadiazole-5-carboxamide(I-190)

To a solution of methyl3-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1,2,4-oxadiazole-5-carboxylate(100 mg, 0.33 mmol) and DIPEA (106 mg, 0.825 mmol) in MeOH (10 mL) wasadded (7-chloroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride (88mg, 0.4 mmol). The reaction mixture was concentrated to give a residue,which was partitioned between DCM (30 mL) and H₂O (30 mL). The layerswere separated and the aqueous phase was extracted with DCM (30×2 mL).The combined organic phase was washed with brine (20 mL), dried overNa₂SO₄, and concentrated to give the crude product., which was purifiedby silica gel chromatography (DCM/MeOH=10/1) to giveN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-3-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1,2,4-oxadiazole-5-carboxamide(11 mg, yield: 7.3%) as an off-white solid. ESI-MS [M+H]⁺: 448.0.Purity: 99.78 (214 nm), 99.69 (254 nm). ¹H NMR (400 MHz, DMSO-d₆) δ 9.81(s, 1H), 8.35-8.26 (m, 3H), 7.82 (s, 1H), 7.72 (s, 1H), 7.35 (d, J=9.3Hz, 1H), 6.96 (d, J=9.3 Hz, 1H), 6.67 (d, J=7.4 Hz, 1H), 4.62 (d, J=5.5Hz, 2H), 4.25 (s, 2H), 1.96-1.87 (m, 1H), 0.94-0.88 (m, 2H), 0.69-0.63(m, 2H).

Example 191

Synthesis of 2-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)acetonitrile

A mixture of ethyl 5-bromobenzofuran-2-carboxylate (538 mg, 2 mmol),cyclopropylboronic acid (223 mg, 2.6 mmol), Pd(OAc)₂ (23 mg, 0.01 mmol),PCy₃ (56 mg, 0.2 mmol) and K₃PO₄ (648 mg, 3 mmol) in toluene (17 mL) andH₂O (2 mL) was degassed with nitrogen and stirred under reflux undernitrogen atmosphere overnight. The reaction mixture was partitionedbetween EtOAc (30 mL) and H₂O (20 mL). The layers were separated and theaqueous phase was extracted with EtOAc (30 mL×3). The combined organiclayer were washed with brine (25 mL), dried over Na₂SO₄, filtered andconcentrated to give the crude product which was purified by columnchromatography (MeOH/DCM=100/1) to get the product ethyl5-cyclopropylbenzofuran-2-carboxylate (369 mg, 85.4%) as a yellow solid.ESI-MS [M+H]⁺: 217.2

Synthesis of Ethyl (5-cyclopropylbenzofuran-2-yl)methanol

To a solution ethyl 5-cyclopropylbenzofuran-2-carboxylate (369 mg, 1.7mmol) in THF (10 mL) was added LiAlH₄ (121 mg, 3.2 mmol). The resultingmixture was stirred at 0° C. for 2 h. The reaction was quenchedsequentially with H₂O (0.5 mL), 15% NaOH (0.5 mL), and H₂O (1.5 mL). Theresulting mixture was filtered and the filtrate was concentrated to givethe crude product (5-cyclopropylbenzofuran-2-yl)methanol (305 mg, 95%)as a yellow oil which was used for next step directly. ESI-MS [M+H]⁺:189.1

Synthesis of 2-(azidomethyl)-5-cyclopropylbenzofuran

To a stirring solution of (5-cyclopropylbenzofuran-2-yl)methanol (305mg, 1.6 mmol) and DPPA (528 mg, 1.92 mmol) in THF (20 mL) was added DBU(291 mg, 1.92 mmol) under 0 C. The resulting mixture was stirred at RTovernight. Water (30 mL) was added and extracted with EtOAc (30 mL×3).The combined organic layers were washed with brine, dried over Na₂SO₄,filtered and concentrated. The residue was purified by flash columnchromatography (DCM/MeOH=20/1) to give the2-(azidomethyl)-5-cyclopropylbenzofuran (250 mg, 72.3%) as a pale-yellowoil. ESI-MS [M+H]⁺: 214.8

Synthesis of Methyl1-((5-cyclopropylbenzofuran-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate

A solution of 2-(azidomethyl)-5-cyclopropylbenzofuran (250 mg, 1.17mmol) in t-BuOH (5 mL) and H₂O (5 mL) was added CuSO₄-5H₂O (58 mg, 0.234mmol), sodium ascorbate (70 mg, 0.347 mmol) and ethyl propiolate (226mg, 2.31 mmol). The resulting mixture was stirred at RT for 15 h. Thereaction mixture was concentrated to get the crude product which waspurified by flash column chromatography (0-3% MeOH in DCM) to give theproduct methyl1-((5-cyclopropylbenzofuran-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(287 mg, 82%) as an off-yellow oil. ESI-MS [M+H]⁺: 298.1.

Synthesis of1-((5-cyclopropylbenzofuran-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicAcid

A solution of ethyl methyl1-((5-cyclopropylbenzofuran-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(287 mg, 0.96 mmol) in THF (5 mL) and MeOH (5 mL) was added with asolution of NaOH (83 mg, 2.08 mmol) in H₂O (5 mL) at RT and stirred for2 h. The volatile was removed in vacuo and the aqueous phase wasacidified to pH 4-5 with 2N HCl. The precipitate was filtered and thesolid was washed with H₂O (3 mL*3). The solid was dried to give1-((5-cyclopropylbenzofuran-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (160 mg, 58%) as a light yellow solid. ESI-MS [M+H]⁺: 284.1.

Synthesis ofN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((5-cyclopropylbenzofuran-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(I-191)

To a mixture of1-((5-cyclopropylbenzofuran-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (160 mg, 0.56 mmol), HATU (159 mg, 0.42 mmol) and DIPEA (147 mg,1.14 mmol) in DMF (3 mL) was added(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride(90 mg, 0.38 mmol) was stirred at RT for 15 h. The reaction mixture wasconcentrated to get a residue. which was purified by flash columnchromatography (0-8% MeOH in DCM) and then prep-TLC (DCM/MeOH=15/1) togive the productN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((5-cyclopropylbenzofuran-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(128 mg, 49%) as an off-white solid. ESI-MS [M+H]⁺: 465.2. Purity: 98.89(214 nm), 98.63 (254 nm). ¹H NMR (400 MHz, DMSO-d₆) δ 8.74 (t, J=5.2 Hz,1H), 8.63 (s, 1H), 8.44 (s, 1H), 8.20 (d, J=7.3 Hz, 1H), 7.40 (d, J=8.5Hz, 1H), 7.33 (s, 1H), 7.04 (d, I=8.6 Hz, 1H), 6.93 (s, 1H), 6.76 (t,J=6.8 Hz, 1H), 5.87 (s, 2H), 4.70 (d, J=5.2 Hz, 2H), 2.05-1.91 (m, 1H),0.97-0.90 (m, 2H), 0.68-0.62 (m, 2H).

Example 192

Synthesis ofN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(difluoromethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(I-192)

To the suspension ofN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-formylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(70 mg, 0.14 mmol) in DCM (3 mL) was added BAST (94 mg, 0.43 mmol) at 0°C. The reaction mixture was warmed to RT and stirred for 3 h. Then thereaction was quenched with sat. NaHCO₃ (30 mL), and extracted with DCM(30 mL×3). The combined organic layer was washed with brine, dried overNa₂SO₄ and concentrated to give the crude, which was purified byprep-HPLC (eluent: DCM/MeOH=10/1) to affordedN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(difluoromethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(10 mg, yield: 13.7%) as a white solid. ESI-MS [M+H]⁺: 515.1. Purity:99.23 (214 nm), 100 (254 nm). ¹H NMR (400 MHz, DMSO-d₆) δ 8.72 (t, J=5.3Hz, 1H), 8.56 (s, 1H), 8.51 (s, 1H), 8.44 (d, J=2.3 Hz, 1H), 8.20 (d,J=7.4 Hz, 1H), 7.92 (s, 1H), 7.44-7.15 (m, 2H), 6.76 (t, J=6.9 Hz, 1H),5.78 (s, 2H), 4.70 (d, J=5.4 Hz, 2H), 2.05-1.97 (m, 1H), 0.98-0.92 (m,2H), 0.74-0.68 (m, 2H).

Example 193

Synthesis ofN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(hydroxymethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide

To a solution of1-((6-cyclopropyl-8-(hydroxymethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (313 mg, 1 mmol),(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride(307 mg, 1.3 mmol) and HATU (570 mg, 1.5 mmol) in DMF (10 mL) was addedDIPEA (387 mg, 3 mmol). The resulting mixture was stirred at RT for 14h. The reaction was poured into H₂O (75 mL) and white solid was formed.The mixture was filtered and dried to give theN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(hydroxymethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamideas a yellow solid (400 mg, 80.9%). ESI-MS [M+H]⁺: 495.2.

Synthesis ofN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((8-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide

To a solution ofN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(hydroxymethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(400 mg, 0.81 mmol) in DCM (25 mL) was added SOCl₂ (3 mL). The resultingmixture was stirred at RT for 5 h. The reaction was concentrated invacuo to give theN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((8-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamideas a yellow solid, which was used into next step without furtherpurification. (520 mg crude). ESI-MS [M+H]⁺: 513.2

Synthesis of Ethyl1-((2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)methyl)-1H-pyrazole-4-carboxylate

A mixture ofN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((8-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(100 mg, 0.19 mmol), ethyl 1H-pyrazole-4-carboxylate (26 mg, 0.19 mmol)and Cs₂CO₃ (123 mg, 0.38 mmol) in DMF (10 mL) was stirred at RT for 14h. The resulting mixture was poured into H₂O (50 mL), extracted withEtOAc (75 mL×3). The combined organic layers were washed with brine,dried over Na₂SO₄, concentrated in vacuo to give the crude, which waspurified with Prep-TLC (DCM/MeOH=10/1) to give the ethyl1-((2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)methyl)-1H-pyrazole-4-carboxylateas a white solid. (65 mg, 54%). ESI-MS [M+H]⁺: 617.2.

Synthesis of1-((2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)methyl)-1H-pyrazole-4-carboxylicacid (I-193)

To a solution of ethyl1-((2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)methyl)-1H-pyrazole-4-carboxylate(65 mg, 0.11 mmol) in THF/H₂O (7 mL/7 mL) was added LiOH.H₂O (11 mg,0.25 mmol). The resulting mixture was stirred at RT for 12 h. Thereaction was concentrated in vacuo to give the crude, which was purifiedwith Prep-HPCL to give the1-((2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)methyl)-1H-pyrazole-4-carboxylicacid (15 mg, 23%). ESI-MS [M+H]⁺: 589.2. Purity: 98.79% (214 nm), 98.89%(254 nm). ¹H NMR (400 MHz, DMSO-d₆) δ 8.73 (t, J=5.2 Hz, 1H), 8.57 (s,1H), 8.46 (s, 1H), 8.34 (s, 1H), 8.31 (s, 1H), 8.21 (d, J=7.4 Hz, 1H),7.85 (s, 1H), 7.82 (s, 1H), 6.77 (t, J=6.9 Hz, 1H), 6.67 (s, 1H), 5.76(s, 2H), 5.59 (s, 2H), 4.71 (d, J=5.3 Hz, 2H), 1.92-1.85 (m, 1H),0.92-0.87 (m, 2H), 0.60-0.57 (m, 2H).

Example 194

Synthesis of1-((8-(2-(1H-tetrazol-5-yl)ethyl)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(I-194)

To a mixture ofN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((8-(2-cyanoethyl)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(100 mg, 0.2 mmol) and NaN₃ (67 mg, 1 mol) in n-BuOH (2 mL) was addedZnCl₂ (1 M in THF, 0.4 mL). The mixture was stirred at 110° C. for 3 h.The reaction was concentrated in vacuo to give the crude which waspurified by Prep-HPLC (eluent: DCM/MeOH=10/1) to give1-((8-(2-(1H-tetrazol-5-yl)ethyl)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(4 mg, yield: 4%) as an off-white solid. ESI-MS [M+H]⁺: 543.2. Purity:96.8 (214 nm), 95.0 (254 nm). ¹H NMR (400 MHz, DMSO-d₆) δ 8.93 (t, J=5.8Hz, 1H), 8.57 (s, 1H), 8.31-8.29 (m, 2H), 8.20 (s, 1H), 7.84 (s, 1H),7.77 (s, 1H), 6.75 (s, 1H), 6.64 (dd, J=7.4, 1.8 Hz, 1H), 5.74 (s, 2H),4.61 (d, J=5.8 Hz, 2H), 3.23 (s, 4H), 1.90-1.82 (m, 1H), 0.92-0.84 (m,2H), 0.63-0.56 (m, 2H).

Example 195

Synthesis of Ethyl 6-cyclopropyl-1H-indole-2-carboxylate

The mixture of ethyl 6-bromo-1H-indole-2-carboxylate (3.5 g, 13.05mmol), cyclopropylboronic acid (2.24 g, 26.11 mmol), Pd(OAc)₂ (146 mg,0.653 mmol), SPhos (536 mg, 1.31 mmol) and K₃PO₄ (8.31 g, 39.15 mmol) intoluene (60 mL) and H₂O (10 mL) was stirred at 100° C. for 16 h underN₂. The reaction mixture was filtered and washed with EtOAc (20 mL). Thefiltrate was concentrated and diluted with H₂O (100 mL), extracted withEtOAc (100 mL×3), the combined organic layers were concentrated andpurified by silica gel chromatography (EA/PE=1/3) to give ethyl6-cyclopropyl-1H-indole-2-carboxylate (2.8 g, yield: 93%) as a yellowsolid. ESI-MS [M+H]⁺: 230.1.

Synthesis of Ethyl 3-bromo-6-cyclopropyl-1H-indole-2-carboxylate

To a stirred solution of ethyl 6-cyclopropyl-1H-indole-2-carboxylate(2.8 g, 12.2 mmol) in THF (60 mL) was added NBS (2.79 g, 15.7 mmol) inportions at 0° C. The mixture was stirred at 25° C. for 2 h. Thereaction mixture was diluted in EtOAc (100 mL), washed with NaHCO₃aqueous (100 mL) and brine (100 mL), dried over Na₂SO₄, concentrated anddried in vacuo to give ethyl3-bromo-6-cyclopropyl-1H-indole-2-carboxylate (3.5 g, 94%) as a yellowsolid. ESI-MS [M+Na]⁺: 330.0.

Synthesis of Ethyl3-bromo-6-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-2-carboxylate

To a stirred solution of NaH (564 mg, 14.1 mmol) in THF (20 mL) wasadded dropwise of the solution of ethyl3-bromo-6-cyclopropyl-1H-indole-2-carboxylate (2.9 g, 9.41 mmol) in THF(28 mL) at 0° C. The mixture was stirred at 0° C. for 10 min and SEMCl(2.04 g, 12.24 mmol) was added dropwise at 0° C. The mixture was stirredat 25° C. for 2 h. The reaction mixture was quenched with H₂O (50 mL)and extracted with EtOAc (80 mL×2). The combined organic layers werewashed with brine (150 mL), dried over Na₂SO₄, concentrated and dried invacuo to give ethyl3-bromo-6-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-2-carboxylate(3.8 g, yield: 93%) as a light brown syrup. ESI-MS [M+Na]⁺: 460.1.

Synthesis of(3-bromo-6-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-2-yl)methanol

To a stirred solution of ethyl3-bromo-6-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-2-carboxylate(750 mg, 1.71 mmol) in DCM (30 mL) was added dropwise DIBAL-H (6.8 mL, 1M in DCM, 6.8 mmol) at 0° C. The mixture was stirred at 0° C. for 1 h.The reaction mixture was quenched with NH₄Cl aqueous (30 mL) andextracted with DCM (30 mL×3). The combined organics was washed withbrine (90 mL), dried over Na₂SO₄, and purified by silica gelchromatography (EA/PE=1/2) to give(3-bromo-6-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-2-yl)methanol(450 mg, yield: 66%) as a colorless syrup. ESI-MS [M+Na]⁺: 418.0.

Synthesis of2-(azidomethyl)-3-bromo-6-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole

To a stirred solution of(3-bromo-6-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-2-yl)methanol(400 mg, 1.01 mmol) and DPPA (834 mg, 3.03 mmol) in DCM (15 mL) wasadded dropwise the solution of DBU (500 mg, 3.03 mmol) in DCM (1 mL) at0° C. The mixture was stirred at 25° C. for 16 h. The reaction mixturewas concentrated and purified by silica gel chromatography (EA/PE=1/5)to give2-(azidomethyl)-3-bromo-6-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole(270 mg, yield: 64%) as a yellow syrup. ESI-MS [M+H]⁺: 421.0.

Synthesis of tert-butyl1-((3-bromo-6-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate

The mixture of2-(azidomethyl)-3-bromo-6-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole(270 mg, 0.64 mmol), ethyl isobutyrate (105 mg, 0.832 mmol), CuSO₄ (51mg, 0.32 mmol) and sodium ascorbate (63 mg, 0.32 mmol) in t-BuOH (5 mL)and H₂O (5 mL) was stirred at 25° C. for 16 h. t-BuOH was removed anddiluted in H₂O (30 mL), extracted with DCM (30 mL×3). The combinedorganics was washed with brine (60 mL), dried over Na₂SO₄, concentratedand purified by silica gel chromatography (EA/PE=1/1) to affordtert-butyl1-((3-bromo-6-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(270 mg, yield: 77%) as a yellow solid. ESI-MS [M+Na]⁺: 569.1.

Synthesis of Methyl2-((4-(tert-butoxycarbonyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-3-carboxylate

A mixture of tert-butyl1-((3-bromo-6-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(270 mg, 0.493 mmol), Pd(dppf)Cl₂ (36 mg, 0.049 mmol) and Et₃N (748 mg,7.40 mmol) in MeOH (25 mL) was stirred at 75° C. for 40 h under CO(balloon). The reaction mixture was concentrated and purified by silicagel chromatography (EA/PE=1/5) to afford methyl2-((4-(tert-butoxycarbonyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-3-carboxylate(70 mg, yield: 27%) as a yellow solid. ESI-MS [M+Na]⁺: 549.2.

Synthesis of1-((6-cyclopropyl-1-(hydroxymethyl)-3-(methoxycarbonyl)-1H-indol-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicAcid

A mixture of methyl2-((4-(tert-butoxycarbonyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-3-carboxylate(50 mg, 0.095 mmol) and TFA (0.3 mL) in DCM (2 mL) was stirred at 25° C.for 16 h. The reaction mixture was concentrated and dried in vacuo togive1-((6-cyclopropyl-1-(hydroxymethyl)-3-(methoxycarbonyl)-1H-indol-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (35 mg, crude) as a purple solid. ESI-MS [M+Na]⁺: 341.1.

Synthesis of Methyl2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropyl-1H-indole-3-carboxylate(I-272)

The mixture of1-((6-cyclopropyl-1-(hydroxymethyl)-3-(methoxycarbonyl)-1H-indol-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (35 mg, crude),(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride(25 mg, 0.105 mmol), EDCI (36 mg, 0.19 mmol), HOBT (26 mg, 0.19 mmol)and DIPEA (123 mg, 0.95 mmol) in DMF (2 mL) was stirred at 25° C. for 16h. The reaction mixture was poured into H₂O (20 mL) and the precipitatewas collected, dried in vacuo and purified by silica gel chromatography(EA/MeOH=40/1) to give methyl2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropyl-1H-indole-3-carboxylate(14 mg, yield: 28%) as a white solid. ESI-MS [M+H]⁺: 522.1. Purity:96.95% (214 nm), 96.72% (254 nm). ¹H NMR (400 MHz, DMSO-d₆) δ 12.06 (s,1H), 8.73 (t, J=5.5 Hz, 1H), 8.53 (s, 1H), 8.43 (d, J=2.4 Hz, 1H), 8.20(d, J=7.4 Hz, 1H), 7.83 (d, J=8.3 Hz, 1H), 7.12 (s, 1H), 6.94 (dd,J=8.4, 1.5 Hz, 1H), 6.78-6.73 (m, 1H), 6.06 (s, 2H), 4.69 (d, J=5.5 Hz,2H), 3.84 (s, 3H), 2.05-1.96 (m, 1H), 0.98-0.91 (m, 2H), 0.69-0.62 (m,2H).

Example 196

Synthesis of Ethyl2-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)oxazole-4-carboxylate

The mixture of 2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine(2.06 g, 10.0 mmol), ethyl oxazole-4-carboxylate (2.82 g, 20.0 mmol),(2-biphenyl)dicyclohexylphosphine (350 mg, 1.0 mmol), Pd(OAc)₂ (224 mg,1.0 mmol) and Cs₂CO₃ (6.52 g, 20.0 mmol) in dioxane (30 mL) was degassedwith N₂ and stirred at 100° C. for 18 h. The reaction mixture was cooledto RT and diluted with H₂O (100 mL). Then extracted with EtOAc (100mL*3). The combined organic layer was washed with brine, dried overNa₂SO₄ and concentrated. The residue was purified by flash columnchromatography to afforded ethyl2-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)oxazole-4-carboxylate(420 mg, yield: 13.5%) as a brown oil. ESI-MS [M+H]⁺: 312.3.

Synthesis of2-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)oxazole-4-carboxylicAcid

A mixture of ethyl2-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)oxazole-4-carboxylate(210 mg, 0.68 mmol) and LiOH.H₂O (142 mg, 3.38 mmol) in THF/H₂O/EtOH (5mL/5 mL/5 mL) was degassed with N₂ and stirred at 50° C. for 18 h. Thereaction mixture was cooled to RT and adjusted to pH-3. Then it wasdiluted with H₂O (50 mL) and extracted with DCM/MeOH (10:1, 30 mL*5).The combined organic layer was washed with brine, dried over Na₂SO₄ andconcentrated to afforded2-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)oxazole-4-carboxylicacid (220 mg, crude) which was used in next step directly. ESI-MS[M+H]⁺: 284.2

Synthesis ofN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-2-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)oxazole-4-carboxamide(I-196)

The mixture of2-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)oxazole-4-carboxylicacid (110 mg, 0.34 mmol),(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride(127 mg, 0.51 mmol), HOBT (55 mg, 0.41 mmol), EDCI (78 mg, 0.41 mmol)and DIPEA (132 mg, 1.02 mmol) in DMF (3 mL) was stirred at to RT for 18h. The reaction mixture was diluted with H₂O (30 mL) then it wasextracted with EtOAc (30 mL*3). The combined organic layer was washedwith brine, dried over Na₂SO₄ and concentrated. The residue was purifiedby prep-HPLC to affordN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-2-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)oxazole-4-carboxamide(8 mg) as a white solid. ESI-MS [M+H]⁺: 465.1. Purity: 97.17 (214 nm),96.01 (254 nm). ¹H NMR (400 MHz, DMSO-d₆) δ 8.50 (s, 1H), 8.45 (d, J=1.7Hz, 1H), 8.39 (t, J=5.2 Hz, 1H), 8.30 (s, 1H), 8.21 (d, J=7.4 Hz, 1H),7.73 (s, 1H), 7.36 (d, J=9.3 Hz, 1H), 6.96 (d, J=9.0 Hz, 1H), 6.76 (t,J=6.9 Hz, 1H), 4.68 (d, J=5.3 Hz, 2H), 4.25 (s, 2H), 1.96-1.87 (m Hz,1H), 0.95-0.88 (m, 2H), 0.69-0.63 (m, 2H).

Example 197

Synthesis of 6-chlorobenzofuran-2-carboxylic Acid

A mixture of 4-chloro-2-hydroxybenzaldehyde (156 mg, 1 mmol), ethyl2-chloroacetate (123 mg, 1 mmol) and K₂CO₃ (553 mg, 4 mmol) in DMF (2mL) was stirred at 130° C. for 4 h. Water (30 mL) was added andextracted with EtOAc (50 mL). The H₂O layer was acidified with HCl (6 M)to pH 3, then extracted with EtOAc (50 mL*3). The combined organic layerwas washed by brine (50 mL*2), dried over Na₂SO₄, and concentrated togive 6-chlorobenzofuran-2-carboxylic acid (196 mg, yield: 100%) as ayellow solid. ESI-MS [M+H]⁺: 197.1.

Synthesis of (6-chlorobenzofuran-2-yl)methanol

To a solution of 6-chlorobenzofuran-2-carboxylic acid (196 mg, 1 mmol)in THF was added BH₃ (2.5 mL, 1 M in THF, 2.5 mmol) dropwise at 0° C.The reaction mixture was stirred at RT for 16 h, CH₃OH (5 mL) was addedat 0° C., then further stirred at RT for 2 h, and concentrated to give(6-chlorobenzofuran-2-yl)methanol (182 mg, crude) as a yellow oil whichwas used in next step directly. ESI-MS [M−17]⁺: 165.1.

Synthesis of 6-chloro-2-(chloromethyl)benzofuran

A mixture of (6-chlorobenzofuran-2-yl)methanol (182 mg, crude from laststep) and SOCl₂ (714 mg, 6 mmol) in DCM (2 mL) was stirred at RT for 3h. Concentration and purification by silica gel chromatography(PE/EA=10/1) yielded 6-chloro-2-(chloromethyl)benzofuran (60 mg, yield:30%) as a white solid, which was used into next step withoutpurification.

Synthesis of 2-(azidomethyl)-6-chlorobenzofuran

A mixture of 6-chloro-2-(chloromethyl)benzofuran (60 mg, 0.29) and NaN₃(25 mg, 0.36 mmol) in DMF (2 mL) was stirred at RT for 3 h. Water (20mL) was added and extracted with EtOAc (30 mL*3). The combined organiclayers were washed by brine (20 mL), dried over Na₂SO₄, concentrated togive 2-(azidomethyl)-6-chlorobenzofuran (60 mg, crude) as a yellow oilwhich was used in next step directly.

Synthesis of Ethyl1-((6-chlorobenzofuran-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate

A mixture of 2-(azidomethyl)-6-chlorobenzofuran (60 mg, crude), ethylpropiolate (84 mg, 0.85 mmol), CuSO₄ (27 mg, 0.17 mmol) and sodiumascorbate (30 mg, 0.17 mmol) in H₂O/t-BuOH (2 mL/2 mL) was stirred at RTfor 3 h. Concentrated and H₂O (20 mL) was added, then extracted withEtOAc (20 mL*5), the combined organic layers were washed by brine (20mL), dried over Na₂SO₄ and concentrated. The residue was purified byflash column chromatography to give ethyl1-((6-chlorobenzofuran-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate (50mg, yield: 55% over 2 steps) as a yellow solid. ESI-MS [M+H]⁺: 306.1.

Synthesis of1-((6-chlorobenzofuran-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic Acid

A mixture of ethyl1-((6-chlorobenzofuran-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate (50mg, 0.15 mmol) and LiOH.H₂O (13 mg, 0.32 mmol) in THF/EtOH/H₂O (2 mL/2mL/1 mL) was stirred at 50° C. for 3 h. Then pH value was adjust to 4 byadding HCl (2 M), the concentrated to give1-((6-chlorobenzofuran-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid(70 mg, crude) as a white solid. ESI-MS [M+H]⁺: 300.0

Synthesis ofN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-chlorobenzofuran-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(I-197)

A mixture of1-((6-chlorobenzofuran-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid(70 mg, crude from last step),(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride(39 mg, 0.16 mmol), HOBT (43 mg, 0.32 mmol), EDCI (61 mg, 0.32 mmol) andDIPEA (103 mg, 0.8 mmol) in DMF (2.5 mL) was stirred at RT for 16 h.Water (10 mL) was added and solid forms. The solid was filtered andwashed with H₂O (3 mL*3) and dried to giveN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-chlorobenzofuran-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(50 mg, yield: 72% over 2 steps) as a white solid. ESI-MS [M+H]⁺: 459.0.Purity: 100 (214 nm), 100 (254 nm). ¹H NMR (400 MHz, DMSO-d₆) δ 8.76 (t,J=5.4 Hz, 1H), 8.65 (s, 1H), 8.44 (d, J=2.3 Hz, 1H), 8.20 (d, J=7.4 Hz,1H), 7.75 (s, 1H), 7.67 (d, J=8.3 Hz, 1H), 7.31 (dd, J=8.3, J=1.8 Hz,1H), 7.06 (s, 1H), 6.77-6.74 (m, 1H), 5.91 (s, 2H), 4.70 (d, J=5.5 Hz,2H).

Example 198

Synthesis ofN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-(1-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)ethyl)-1H-1,2,3-triazole-4-carboxamide(I-198)

A mixture of1-(1-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)ethyl)-1H-1,2,3-triazole-4-carboxylicacid (200 mg, 0.67 mmol),(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride(190 mg, 0.81 mmol), HOBT (181 mg, 1.34 mmol), EDCI (257 mg, 1.34 mmol)and DIPEA (432 mg, 5.0 mmol) in DMF (6 mL) was stirred at RT for 16 h.Water (30 mL) was added to the reaction, extracted by EtOAc (30 mL×3).The organic layers were washed by brine, dried over Na₂SO₄, filtered,and concentrated to give the crude, which was purified by Prep-TLC(DCM/MeOH=10/1) to obtainedN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-(1-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)ethyl)-1H-1,2,3-triazole-4-carboxamideas a white solid (60 mg, yield: 19%). ESI-MS [M+H]⁺: 479.1. Purity:96.47 (214 nm), 97.74 (254 nm). ¹H NMR (400 MHz, DMSO-d₆) δ 8.68 (t,J=6.0 Hz, 1H), 8.59 (s, 1H), 8.44 (d, J=4 Hz, 1H), 8.32 (d, J=7.4 Hz,1H), 8.20 (d, J=4.0 Hz, 1H), 7.77 (s, 1H), 7.42 (d, J=12 Hz, 1H), 7.01(dd, J=4.0, 8.0 Hz, 1H), 6.76 (t, J=8.0 Hz, 1H), 6.12 (q, J=8.0 Hz, 1H),4.70 (d, J=4.0 Hz, 2H), 1.93-1.91 (m, 4H), 0.94-0.89 (m, 2H), 0.68-0.64(m, 2H).

Example 199

Synthesis of tert-butyl1-((8-(4-((tert-butyldimethylsilyl)oxy)-1-methoxy-1-oxobutan-2-yl)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate

To a stirred suspension of NaH (239 mg, 5.97 mmol, 60%) in DMF (12 mL)was added a solution of tert-butyl1-((6-cyclopropyl-8-(2-methoxy-2-oxoethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(490 mg, 1.19 mmol) in DMF (2 mL) at 0° C. under N₂, and the mixture wasstirred for 10 min. Then a solution of(2-bromoethoxy)(tert-butyl)dimethylsilane (1.14 g, 4.77 mmol) in DMF (2mL) was added dropwise and the resulting mixture was stirred for 20 minat 0° C. The reaction was quenched with ice H₂O (60 mL) and extractedwith EtOAc (50 mL×3). The combined organic layers was washed with brine(100 mL), dried over Na₂SO₄, concentrated to give the crude, which waspurified by silica gel chromatography (EA/PE=1/2) to give tert-butyl1-((8-(4-((tert-butyldimethylsilyl)oxy)-1-methoxy-1-oxobutan-2-yl)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(150 mg, yield: 22%) as a yellow syrup. ESI-MS [M+H]⁺: 570.3.

Synthesis of tert-butyl1-((6-cyclopropyl-8-(2-oxotetrahydrofuran-3-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate

To a stirred suspension of tert-butyl1-((8-(4-((tert-butyldimethylsilyl)oxy)-1-methoxy-1-oxobutan-2-yl)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(150 mg, 0.26 mmol) in THF (5 mL) was added HCl (3 M, 0.1 mL) and themixture was stirred at 23° C. for 48 h. The reaction mixture was dilutedin EtOAc (50 mL), washed with NaHCO₃ aqueous solution and brine (50 mL),dried over Na₂SO₄, concentrated to give the crude, which was purified bysilica gel chromatography (EA/PE=2/1) to give tert-butyl1-((6-cyclopropyl-8-(2-oxotetrahydrofuran-3-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(95 mg, 86%) as a colorless syrup. ESI-MS [M+H]⁺: 424.2.

Synthesis of1-((6-cyclopropyl-8-(2-oxotetrahydrofuran-3-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicAcid

A mixture of tert-butyl1-((6-cyclopropyl-8-(2-oxotetrahydrofuran-3-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(95 mg, 0.224 mmol) and TFA (0.5 mL) in DCM (1.5 mL) was stirred at RTfor 1 h. The reaction mixture was concentrated and dried in vacuo togive1-((6-cyclopropyl-8-(2-oxotetrahydrofuran-3-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (90 mg, crude) as a yellow solid, which was used into next stepwithout further purification. ESI-MS [M+H]⁺: 368.1.

Synthesis ofN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(2-oxotetrahydrofuran-3-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(I-199)

A mixture of1-((6-cyclopropyl-8-(2-oxotetrahydrofuran-3-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (90 mg, crude),(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride(32 mg, 0.136 mmol), EDCI (39 mg, 0.204 mmol), HOBT (28 mg, 0.204 mmol)and DIPEA (176 mg, 1.36 mmol) in DMF (2 mL) was stirred at 25° C. for 16h. The reaction mixture was poured into H₂O (30 mL) and the precipitatewas collected, washed with H₂O (30 mL), dried to give the crude, whichwas purified by silica gel chromatography (DCM/MeOH=20/1) to giveN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(2-oxotetrahydrofuran-3-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(33 mg, yield: 44%) as a white solid. ESI-MS [M+H]⁺: 549.1. Purity:99.48 (214 nm), 99.64 (254 nm). ¹H NMR (400 MHz, DMSO-d₆) δ 8.71 (t,J=5.5 Hz, 1H), 8.53 (s, 1H), 8.44 (d, J=2.4 Hz, 1H), 8.30 (d, J=1.3 Hz,1H), 8.21 (d, J=7.4 Hz, 1H), 7.79 (s, 1H), 7.02 (d, J=1.5 Hz, 1H),6.80-6.73 (m, 1H), 5.74 (s, 2H), 4.70 (d, J=5.5 Hz, 2H), 4.55-4.48 (m,1H), 4.47-4.20 (m, 2H), 2.72-2.60 (m, 1H), 2.59-2.53 (m, 1H), 1.96-1.89(m, 1H), 0.97-0.88 (m, 2H), 0.70-0.65 (m, 2H).

Example 200

Synthesis ofN-((7-bromo-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-fluoroimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(I-200)

A mixture of1-((6-cyclopropyl-8-fluoroimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (60 mg, 0.2 mmol),(7-bromo-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride(56 mg, 0.2 mmol), EDCI (58 mg, 0.3 mmol), HOBT (41 mg, 0.3 mmol) andDIPEA (155 mg, 1.2 mmol) in DMF (3 mL) was stirred at 25° C. for 16 h.The reaction mixture was poured into H₂O (40 mL) and the precipitate wascollected, washed with H₂O (30 mL), dried in vacuo to give the crude,which was purified by prep-TLC (DCM/MeOH=10/1) to giveN-((7-bromo-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-fluoroimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(66 mg, yield: 63%) as a white solid. ESI-MS [M+H]+: 527.0. Purity:98.44 (214 nm), 99.43 (254 nm). ¹H NMR (400 MHz, DMSO-d₆) δ 8.71 (t,J=5.4 Hz, 1H), 8.57 (s, 1H), 8.45 (d, J=2.3 Hz, 1H), 8.27 (s, 1H), 8.14(d, J=7.4 Hz, 1H), 7.95 (d, J=2.8 Hz, 1H), 6.95 (d, J=12.4 Hz, 1H),6.86-6.77 (m, 1H), 5.76 (s, 2H), 4.69 (d, J=5.5 Hz, 2H), 1.99-1.90 (m,1H), 0.98-0.89 (m, 2H), 0.74-0.65 (m, 2H).

Example 201

Synthesis of1-((8-((1H-pyrazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(I-201)

A mixture ofN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((8-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(100 mg, 0.19 mmol), 1H-pyrazole (13 mg, 0.19 mmol) and Cs₂CO₃ (124 mg,0.38 mmol) in DMF (5 mL) was stirred at RT for 14 h. H₂O (30 mL) wasadded to the reaction, extracted with EtOAC (30 mL×3). The combinedorganic layers were washed with brine, dried over Na₂SO₄, concentratedin vacuo to give the crude, which was purified with Prep-HPLC to givethe1-((8-((1H-pyrazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-1,2,3-triazole-4-carboxamideas a white solid. (22 mg, 21%). ESI-MS [M+H]⁺: 545.2. Purity: 99.69%(214 nm), 99.66% (254 nm). ¹H NMR (400 MHz, DMSO-d₆) δ 8.71 (t, J=5.4Hz, 1H), 8.56 (s, 1H), 8.45 (d, J=2.4 Hz, 1H), 8.29 (s, 1H), 8.21 (d,J=7.4 Hz, 1H), 7.87-7.86 (m, 2H), 7.45 (d, J=1.4 Hz, 1H), 6.76 (t, J=7.0Hz, 1H), 6.55 (s, 1H), 6.23 (t, J=2.0 Hz, 1H), 5.76 (s, 2H), 5.55 (s,2H), 4.71 (d, J=5.5 Hz, 2H), 1.89-1.82 (m, 1H), 0.90-0.86 (m, 2H),0.57-0.53 (m, 2H).

Example 202

Synthesis ethyl1-((2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)methyl)-1H-pyrazole-3-carboxylate

A mixture ofN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((8-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(100 mg, 0.19 mmol), ethyl 1H-pyrazole-3-carboxylate (27 mg, 0.19 mmol)and Cs₂CO₃ (124 mg, 0.38 mmol) in DMF (10 mL) was stirred at RT for 14h. H₂O (40 mL) was added to the reaction, extracted with EtOAc (40mL×3). The combined organic layers were washed with brine, dried overNa₂SO₄, concentrated in vacuo to give the crude, which was purified withPrep-TLC (DCM/MeOH=10/1) to give the product as a yellow solid. (70 mg,58%). ESI-MS [M+H]⁺: 617.2.

Synthesis1-((2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)methyl)-1H-pyrazole-3-carboxylicacid (I-202)

To a solution of ethyl1-((2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)methyl)-1H-pyrazole-3-carboxylate(70 mg, 0.11 mmol) in THF/H₂O (7 mL/7 mL) was added LiOH.H₂O (13 mg,0.33 mmol). The resulting mixture was stirred at RT for 12 h. Thereaction was acidified to pH 4 by HCl (1 M) then concentrated in vacuoto give a crude residue, which was purified with Prep-HPLC to give the1-((2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)methyl)-1H-pyrazole-3-carboxylicacid as a white solid. (10 mg, 15%). ESI-MS [M+H]⁺: 589.2. Purity: 99.69(214 nm), 99.66 (254 nm). ¹H NMR (400 MHz, DMSO-d₆) 8.73 (t, J=5.3 Hz,1H), 8.58 (s, 1H), 8.45 (d, J=2.1 Hz, 1H), 8.32 (s, 1H), 8.20 (d, J=7.4Hz, 1H), 7.97 (s, 1H), 7.86 (s, 1H), 6.76 (t, J=7.0 Hz, 1H), 6.73 (s,1H), 6.66 (s, 1H), 5.77 (s, 2H), 5.62 (s, 2H), 4.71 (d, J=5.4 Hz, 2H),1.93-1.85 (m, 1H), 0.92-0.85 (m, 2H), 0.59-0.55 (m, 2H).

Example 203

Synthesis of 3-bromo-5-cyclopropylpyridin-2-amine

To a solution of 5-cyclopropylpyridin-2-amine (8.08 g, 60 mmol) in MeCN(200 mL) was added NBS (11.72 g, 66 mmol) in portions at 0° C. during 30min. The mixture was stirred at 0° C. for additional 30 min and thenconcentrated to give the crude, which was purified by silica gelchromatography (PE/EA=5/1 to 4/1) to afford3-bromo-5-cyclopropylpyridin-2-amine as a white solid (8.23 g, yield:64%). ESI-MS [M+H]⁺: 212.8,

Synthesis of8-bromo-2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine

A solution of 3-bromo-5-cyclopropylpyridin-2-amine (8.23 g, 38.6 mmol)and 1,3-dichloropropan-2-one (7.46 g, 57.9 mmol) in EtOAc (80 mL) wasstirred at 70° C. for 48° C. The reaction mixture was diluted with EtOAc(300 mL) and washed with saturate aqueous NaHCO₃ (100 mL). The organiclayer was washed brine, dried over Na₂SO₄, concentrated in vacuo to givethe crude, which was purified with silica gel (EtOAc/PE=1/2) to give (8g, yield: 72.3%) as a yellow solid. ESI-MS [M+H]⁺: 284.8

Synthesis of 2-(azidomethyl)-8-bromo-6-cyclopropylimidazo[1,2-a]pyridine

A solution of8-bromo-2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine (2.85 g, 10mmol) in DMF (30 mL) was added NaN₃ (1.3 g, 20 mmol) and the mixture wasstirred at RT for 15 h. H₂O (100 mL) was added to the reaction,extracted with EtOAc (100 mL×3). The combined organic layers were washedwith brine, dried over Na₂SO₄, filtered, and concentrated in vacuo togive 2-(azidomethyl)-8-bromo-6-cyclopropylimidazo[1,2-a]pyridine as ayellow powder which was used directly for next step without furtherpurification (1.97 g, 67%). ESI-MS [M+H]⁺: 291.9.

Synthesis of Ethyl1-((8-bromo-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate

To a mixture of2-(azidomethyl)-8-bromo-6-cyclopropylimidazo[1,2-a]pyridine (1.97 g, 6.7mmol), ethyl propiolate (1 g, 10 mmol) in tBuOH/H₂O (10 mL/10 mL) wasadded CuSO₄ (320 mg, 2 mmol) and sodium ascorbate (397 mg, 2 mmol). Thereaction mixture was stirred at RT for 5 h. The reaction wasconcentrated to remove tBuOH to give a yellow solid. The precipitate wascollected. The filter cake was washed by H₂O (20 mL×3), followed by MeOH(20 mL), and then dried to give ethyl1-((8-bromo-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylateas a gray solid (1.8 g, 69%). ESI-MS [M+H]⁺: 389.8.

Synthesis of1-((6-cyclopropyl-8-(2-oxopyrrolidin-1-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicAcid

A mixture of ethyl1-((8-bromo-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(78 mg, 0.2 mmol), pyrrolidin-2-one (25.4 mg, 0.3 mmol), Pd₂(dba)₃ (18mg, 0.02 mmol), XantPhos (25 mg, 0.04 mmol) and Cs₂CO₃ (130 mg, 0.4mmol) in DMA (2 mL) in a sealed tube was bubbled with argon for 10 minat RT and then the mixture was heated to 150° C. for 14 h. The mixturewas cooled to RT and then filtered and washed with DCM (30 mL). Water(30 mL) was added to the filtrate, the aqueous phase was separated andextracted with DCM for 2 times and concentrated under reduced pressureto afford crude of1-((6-cyclopropyl-8-(2-oxopyrrolidin-1-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (114 mg, crude) which was used directly for the next step. ESI-MS[M+H]⁺: 366.9.

Synthesis ofN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(2-oxopyrrolidin-1-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(I-203)

To a solution of1-((6-cyclopropyl-8-(2-oxopyrrolidin-1-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (114 mg, crude from previous step) in anhydrous DMF (5 mL) wasadded (7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine (20 mg,0.1 mmol), DIPEA (26 mg, 0.2 mmol), HATU (58 mg, 0.15 mmol) in sequence.The mixture was stirred at RT for 2.5 h. The reaction was partitionedbetween DCM (50 mL) and H₂O (50 mL). The aqueous phase was extractedwith DCM (50 mL×2). The combined organic layers were washed with brine,dried over Na₂SO₄, concentrated by evaporation to give the crude, whichwas purified by prep-HPLC to giveN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(2-oxopyrrolidin-1-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(5.1 mg, 9% over 2 steps). ESI-MS [M+H]⁺: 547.8. Purity: 99.91 (214 nm)99.63 (254 nm). ¹H NMR (400 MHz, CDCl₃) δ 8.24 (s, 1H), 8.10 (s, 1H),7.78 (s, 1H), 7.66 (m, 2H), 7.51 (s, 1H), 7.29 (s, 1H), 6.52 (t, J=6.7Hz, 1H), 5.70 (s, 2H), 4.95 (d, J=5.1 Hz, 2H), 4.23 (t, J=7.0 Hz, 2H),2.63 (t, J=8.1 Hz, 2H), 2.26 (dt, J=15.1, 7.6 Hz, 2H), 1.94-1.85 (m,1H), 1.02-0.93 (m, 2H), 0.70 (m, 2H).

Example 204

Synthesis of lithium1-((8-bromo-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate

To a solution of ethyl1-((8-bromo-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(39.8 mg, 0.1 mmol) in THF (3 mL) and H₂O (3 mL) was added LiOH.H₂O (42mg, 1 mmol) and the mixture was stirred at RT for 16 h. The mixture waslyophilized to afford lithium1-((8-bromo-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylateas as a white solid which was used directly for the next step withoutfurther purification (82 mg crude). ESI-MS [M+H]⁺: 361.8

Synthesis of1-((8-bromo-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(I-204)

The crude of lithium1-((8-bromo-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(82 mg, crude from previous step) in anhydrous DMF (2 mL) was added(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride(22 mg, 0.1 mmol), DIPEA (28.7 mg, 0.2 mmol) and HATU (58.6 mg, 0.15mmol) in sequence. The mixture was stirred at RT for 2 h. The reactionwas poured into H₂O (20 mL) and yellow solid was precipitated. Themixture was filtered and washed with MeOH (20 mL) to afford1-((8-bromo-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-1,2,3-triazole-4-carboxamideas pale yellow solid (18.8 mg, 35% over 2 steps). ESI-MS [M+H]⁺: 542.7.Purity: 97.09 (214 nm) 95.14 (254 nm). ¹H NMR (400 MHz, DMSO-d₆) δ 8.73(brs, 1H), 8.57 (s, 1H), 8.43 (m, 2H), 8.21 (d, J=7.4 Hz, 1H), 7.94 (s,1H), 7.40 (s, 1H), 6.77 (t, J=6.9 Hz, 1H), 5.77 (s, 2H), 4.70 (s, 2H),1.94 (m, 1H), 0.92 (m, 2H), 0.71 (m, 2H).

Example 205

Synthesis of tert-butyl1-((6-cyclopropyl-8-(hydroxymethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate

The mixture of(2-(azidomethyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)methanol (20 g,82.38 mmol), tert-butyl propiolate (10.4 g, 82.38 mmol), CuSO₄ (657 mg,4.12 mmol) and sodium ascorbate (1.63 g, 8.24 mmol) in t-BuOH (100 mL)and H₂O (100 mL) was stirred at 25° C. for 16 h. t-BuOH was removed togive the residue, which was diluted in H₂O (100 mL), extracted with DCM(150 mL×3). The combined organics were washed with brine (300 mL), driedover Na₂SO₄, concentrated to give the crude, which was triturated withEtOAc and dried to afford tert-butyl1-((6-cyclopropyl-8-(hydroxymethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(18 g, yield: 59%) as a light brown solid. ESI-MS [M+H]⁺: 370.1.

Synthesis of tert-butyl1-((8-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate

To a stirred solution of tert-butyl1-((6-cyclopropyl-8-(hydroxymethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(2 g, 5.41 mmol) in DCM (30 mL) was added dropwise SOCl₂ (1.29 g, 10.82mmol) at 0° C. The mixture was stirred at 25° C. for 1 h. The reactionmixture was concentrated and the residue was dissolved in DCM (80 mL),washed with saturated aqueous NaHCO₃ (80 mL) and brine, dried overNa₂SO₄, concentrated to give the crude, which was purified by silica gelchromatography (EtOAc/PE=1/1) to give tert-butyl1-((8-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(1.8 g, yield: 86%) as a light brown solid. ESI-MS [M+H]⁺: 388.1.

Synthesis of tert-butyl1-((6-cyclopropyl-8-(3-ethoxy-2,2-dimethyl-3-oxopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate

To a stirred solution of ethyl isobutyrate (808 mg, 6.96 mmol) in THF(20 mL) was added LDA (3.7 mL, 2 M, 7.4 mmol) dropwise at −40° C. underN₂. After 1 h, the solution of tert-butyl1-((8-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(1.8 g, 4.64 mmol) in THF (15 mL) was added to the reaction above at−78° C. over 30 min. The resulting mixture was stirred at −78° C. foranother 1.5 h. The reaction mixture was quenched with NH₄Cl aqueous (100mL), extracted with EtOAc (100 mL×3). The combined organics were washedwith brine (140 mL), dried over Na₂SO₄, concentrated to give the crude,which was purified by silica gel chromatography (EtOAc/PE=1/2) to givetert-butyl1-((6-cyclopropyl-8-(3-ethoxy-2,2-dimethyl-3-oxopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(1.24 g, yield: 57%) as a colorless syrup. ESI-MS [M+H]⁺: 468.2.

Synthesis of1-((6-cyclopropyl-8-(3-ethoxy-2,2-dimethyl-3-oxopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicAcid

A mixture of tert-butyl1-((6-cyclopropyl-8-(3-ethoxy-2,2-dimethyl-3-oxopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(1.24 g, 2.65 mmol) and HCl in dioxane (10 mL, 4N) was stirred at 25° C.for 18 h. The reaction mixture was concentrated and dried in vacuo toafford give1-((6-cyclopropyl-8-(3-ethoxy-2,2-dimethyl-3-oxopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (1.3 g, yield: 100%) as a colorless syrup. ESI-MS [M+H]⁺: 412.2.

Synthesis of Ethyl3-(2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)-2,2-dimethylpropanoate(I-205)

A mixture of1-((6-cyclopropyl-8-(3-ethoxy-2,2-dimethyl-3-oxopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (61.7 mg, 0.15 mmol),(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride(35.4 mg, 0.15 mmol), EDCI (57.5 mg, 0.3 mmol), HOBT (40.5 mg, 0.3 mmol)and DIPEA (194 mg, 1.5 mmol) in DMF (6 mL) was stirred at 25° C. for 16h. The reaction mixture was poured into H₂O (30 mL) and extracted withEtOAc/THF (40 mL×3, 5/1). The combined organics were washed with brine(70 mL), dried over Na₂SO₄, concentrated to give the crude, which waspurified by silica gel chromatography (DCM/MeOH=20/1) to give ethyl3-(2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)-2,2-dimethylpropanoate(50 mg, yield: 56%) as a pale white solid. ESI-MS [M+H]⁺: 593.2. Purity:99.13 (214 nm), 100 (254 nm). ¹H NMR (400 MHz, DMSO-d₆) δ 8.69 (t, J=5.4Hz, 1H), 8.50 (s, 1H), 8.44 (d, J=2.3 Hz, 1H), 8.26-8.18 (m, 2H), 7.78(s, 1H), 6.78-6.74 (m, 1H), 6.67 (d, J=1.3 Hz, 1H), 5.71 (s, 2H), 4.69(d, J=5.4 Hz, 2H), 3.94 (q, J=7.1 Hz, 2H), 3.09 (s, 2H), 1.93-1.84 (m,1H), 1.16-1.03 (m, 9H), 0.95-0.88 (m, 2H), 0.64-0.57 (m, 2H).

Example 206

Synthesis of3-(2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)-2,2-dimethylpropanoicacid (I-206)

To a solution of ethyl3-(2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)-2,2-dimethylpropanoate(78 mg, 0.13 mmol) and NaOH (52 mg, 1.3 mmol) in DMSO (2 mL) and H₂O (2mL) was stirred at 40° C. for 6 h. The reaction mixture was poured intoH₂O (20 mL). The mixture was acidified to pH 4-5 by HCl (1N) andextracted with EtOAc/THF (30 mL×3, 5/1). The combined organics werewashed with brine (40 mL), dried over Na₂SO₄, concentrated to give thecrude, which was purified by silica gel chromatography (DCM/MeOH=20/1)to give3-(2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)-2,2-dimethylpropanoicacid (30 mg, yield: 40%) as a pale white solid. ESI-MS [M+H]⁺: 565.1.Purity: 100 (214 nm), 100 (254 nm). ¹H NMR (400 MHz, DMSO-d₆) δ 12.44(s, 1H), 8.69 (t, J=5.5 Hz, 1H), 8.51 (s, 1H), 8.44 (d, J=2.4 Hz, 1H),8.24-8.17 (m, 2H), 7.76 (s, 1H), 6.79-6.71 (m, 2H), 5.72 (s, 2H), 4.69(d, J=5.5 Hz, 2H), 3.09 (s, 2H), 1.90-1.83 (m, 1H), 1.08 (s, 6H),0.93-0.88 (m, 2H), 0.65-0.59 (m, 2H).

Example 207

Synthesis of Ethyl 2-((2-amino-5-chloropyridin-3-yl)oxy)acetate

To a mixture of 2-amino-5-chloropyridin-3-ol (2.9 g, 20 mmol) in DMSO(50 mL) was added NaOMe (1.08 g, 20 mmol). The reaction mixture wasstirred at RT for 30 min. Then ethyl 2-bromoacetate (3.34 g, 20 mmol)was added thereto. The mixture was stirred at RT for another 2 h. Water(300 mL) was added to the reaction, extracted with EtOAc (200 mL×3). Thecombined organic phase was washed with brine, dried over Na₂SO₄,filtrated and concentrated to give ethyl2-((2-amino-5-chloropyridin-3-yl)oxy)acetate (4.0 g, yield: 87%) as ayellow oil, which was used into next step without further purification.ESI-MS [M+H]⁺: 231.1.

Synthesis of Ethyl2-((6-chloro-2-(chloromethyl)imidazo[1,2-a]pyridin-8-yl)oxy)acetate

A mixture of ethyl 2-((2-amino-5-chloropyridin-3-yl)oxy)acetate (4.0 g,17.3 mmol) and 1,3-dichloropropan-2-one (6.7 g, 52 mmol) in DMF (50 mL)was stirred at 95° C. for 3 h. After cooled, the reaction was quenchedwith saturated aqueous NaHCO₃ (100 mL) and extracted with EtOAc (200mL×3). The combined organic phase was washed with brine, dried overNa₂SO₄, filtrated and concentrated to give the residue, which waspurified by silica gel chromatography (PE/EA=5/1 to 2/1) to give ethyl2-((6-chloro-2-(chloromethyl)imidazo[1,2-a]pyridin-8-yl)oxy)acetate (900mg, yield: 17.3%) as a yellow solid. ESI-MS [M+H]⁺: 303.1.

Synthesis of Ethyl2-((2-(azidomethyl)-6-chloroimidazo[1,2-a]pyridin-8-yl)oxy)acetate

To a mixture of ethyl2-((6-chloro-2-(chloromethyl)imidazo[1,2-a]pyridin-8-yl)oxy)acetate (900mg, 3 mmol) in DMF (5 mL) was added NaN₃ (234 mg, 3.6 mmol). The mixturewas stirred at RT for 2 h. The reaction was quenched with H₂O (50 mL),extracted with EtOAc (50 mL×3). The combined organic phase was washedwith brine, dried over Na₂SO₄, filtrated and concentrated. The residuewas purified by silica gel chromatography (PE/EA=5/1 to 2/1) to giveethyl 2-((2-(azidomethyl)-6-chloroimidazo[1,2-a]pyridin-8-yl)oxy)acetate(650 mg, yield: 70%) as a yellow solid. ESI-MS [M+H]⁺: 310.1.

Synthesis of tert-butyl1-((6-chloro-8-(2-ethoxy-2-oxoethoxy)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate

To a mixture of ethyl2-((2-(azidomethyl)-6-chloroimidazo[1,2-a]pyridin-8-yl)oxy)acetate (650mg, 2.1 mmol), CuSO₄ (67 mg, 0.42 mmol) and sodium ascorbate (83 mg,0.42 mmol) in t-BuOH/H₂O (10 mL/10 mL) was added tert-butyl propiolate(319 mg, 2.5 mmol). The mixture was stirred at RT for 2 h. Water (50 mL)was added to the reaction and extracted with EtOAc (50 mL×3). Thecombined organic phase was washed with brine, dried over Na₂SO₄,filtrated and concentrated to give the crude, which was triturated withEA/PE (20 mL/20 mL) to give tert-butyl1-((6-chloro-8-(2-ethoxy-2-oxoethoxy)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(850 mg, yield: 93%) as a blue solid. ESI-MS [M+H]⁺: 436.2.

Synthesis of tert-butyl1-((6-cyclopropyl-8-(2-ethoxy-2-oxoethoxy)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate

To a mixture of tert-butyl1-((6-chloro-8-(2-ethoxy-2-oxoethoxy)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(436 mg, 1 mmol), cyclopropylboronic acid (180 mg, 2 mmol) and K₃PO₄(850 mg, 4 mmol) in toluene/H₂O (10 mL/1 mL) was added Pd(OAc)₂ (44 mg,0.2 mmol) and SPhos (82 mg, 0.2 mmol). The mixture was stirred at 95° C.for 16 h under N₂ atmosphere. Water (50 mL) was added to the reactionand extracted with EtOAc (50 mL×3). The combined organic layers werewashed with brine, dried over Na₂SO₄, filtrated and concentrated to givethe crude, which was purified by silica gel chromatography(DCM/MeOH=50/1 to 20/1) to give tert-butyl1-((6-cyclopropyl-8-(2-ethoxy-2-oxoethoxy)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(200 mg, yield: 45%) as a yellow solid. ESI-MS [M+H]⁺: 442.2.

Synthesis of1-((6-cyclopropyl-8-(2-ethoxy-2-oxoethoxy)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicAcid

To a suspension of tert-butyl1-((6-cyclopropyl-8-(2-ethoxy-2-oxoethoxy)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(200 mg, 0.46 mmol) in DCM (8 mL) was added TFA (1 mL). The mixture wasstirred at RT for 3 h. The reaction was concentrated to give1-((6-cyclopropyl-8-(2-ethoxy-2-oxoethoxy)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (200 mg, crude) as a yellow oil, which was used into next stepwithout further purification. ESI-MS [M+H]⁺: 386.1.

Synthesis of Ethyl2-((2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)oxy)acetate(I-207)

To a mixture of1-((6-cyclopropyl-8-(2-ethoxy-2-oxoethoxy)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (100 mg, crude form previous step),(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride(118 mg, 0.5 mmol) and DIPEA (336 mg, 2.6 mmol) in DMF (10 mL) was addedHOBT (140 mg, 1.04 mmol) and EDC (200 mg, 1.04 mmol). The mixture wasstirred at RT for 16 h. Water (50 mL) was added to the reaction andextracted with EtOAc (50 mL×3). The combined organic phase was washedwith brine, dried over Na₂SO₄, filtrated and concentrated. The residuewas purified by Prep-TLC (DCM/MeOH=10/1) to give ethyl2-((2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)oxy)acetate(50 mg, yield: 20%) as a white solid. ESI-MS [M+H]⁺: 567.1. Purity: 95.4(214 nm), 96.5 (254 nm). ¹H NMR (400 MHz, DMSO-d₆) δ 8.70 (t, J=5.4 Hz,1H), 8.54 (s, 1H), 8.44 (d, J=2.4 Hz, 1H), 8.20 (d, J=7.4 Hz, 1H), 8.01(d, J=0.7 Hz, 1H), 7.83 (s, 1H), 6.76 (dd, J=7.3, 6.6 Hz, 1H), 6.35 (d,J=1.2 Hz, 1H), 5.71 (s, 2H), 5.00 (s, 2H), 4.70 (d, J=5.5 Hz, 2H), 4.16(q, J=7.1 Hz, 2H), 1.91-1.84 (m, 1H), 1.19 (t, J=7.1 Hz, 3H), 0.95-0.84(m, 2H), 0.72-0.60 (m, 2H).

Example 208

Synthesis of2-((2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)oxy)aceticacid (I-208)

To a mixture of ethyl2-((2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)oxy)acetate(60 mg, 0.11 mmol) in EtOH/H₂O (2 mL/0.2 mL) was added LiOH.H₂O (13 mg,0.3 mmol). The mixture was stirred at RT for 3 h. The pH of the reactionwas adjusted to 5 by HCl (1N), and white solid was precipitated. Themixture was filtrated and dried to give2-((2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)oxy)aceticacid (35 mg, yield: 59%) as an off-white solid. ESI-MS [M+H]⁺: 539.1.Purity: 98.0 (214 nm), 100.0 (254 nm). ¹H NMR (400 MHz, DMSO-d₆) δ 13.27(s, 1H), 8.76 (t, J=5.4 Hz, 1H), 8.63 (s, 1H), 8.47 (d, J=2.4 Hz, 1H),8.26-8.19 (m, 2H), 8.14-8.12 (m, 1H), 6.91 (s, 1H), 6.77 (dd, J=7.3, 6.6Hz, 1H), 5.87 (s, 2H), 5.03 (s, 2H), 4.71 (d, J=5.5 Hz, 2H), 2.02-1.96(m, 1H), 1.10-0.91 (m, 2H), 0.84-0.67 (m, 2H).

Example 209

Synthesis of Methyl 6-bromopyrazolo[1,5-a]pyrimidine-2-carboxylate

To a solution of methyl 5-amino-1H-pyrazole-3-carboxylate (1 g, 7.09mmol) and con. HCl (0.67 mL, 8.15 mmol) in EtOH (20 mL) was added2-bromomalonaldehyde (1.1 g, 7.37 mmol). The resulting mixture wasstirred at RT for 15 h. The precipitate formed and collected byfiltration and washed with diethyl ether, dried in vacuo to get theproduct methyl 6-bromopyrazolo[1,5-a]pyrimidine-2-carboxylate (1.5 g,82.6%) as a dark yellow solid which was used in next step directly.ESI-MS [M+H]⁺: 255.7, 257.7. ¹H NMR (400 MHz, DMSO-d₆) δ 9.71 (s, 1H),8.76 (s, 1H), 7.27 (s, 1H), 3.91 (s, 3H).

Synthesis of Methyl 6-cyclopropylpyrazolo[1,5-a]pyrimidine-2-carboxylate

A mixture of methyl 6-bromopyrazolo[1,5-a]pyrimidine-2-carboxylate (1.9g, 7.4 mmol), cyclopropylboronic acid (0.83 g, 9.6 mmol), Pd(OAc)₂ (85mg, 0.37 mmol), PCy₃ (207 mg, 0.74 mmol) and K₃PO₄ (2.4 g, 11.1 mmol) intoluene (35 mL) and H₂O (4 mL) was stirred under reflux under nitrogenatmosphere overnight. The reaction mixture was partitioned between EtOAc(50 mL) and H₂O (50 mL). The organic layer were separated and theaqueous phase was extracted with EtOAc (3×100 mL). The combined organiclayers were washed with brine (25 mL), dried over Na₂SO₄, filtered andconcentrated to get the crude product. The crude product was purified bycolumn chromatography (MeOH/DCM=0-1%) to get methyl6-cyclopropylpyrazolo[1,5-a]pyrimidine-2-carboxylate (850 mg, 53%) as ayellow solid. ESI-MS [M+H]⁺: 217.8. ¹H NMR (400 MHz, CDCl₃) δ 8.44 (s,1H), 8.42 (s, 1H), 7.20 (s, 1H), 4.01 (s, 3H), 2.02-1.93 (m, 1H),1.15-1.07 (m, 2H), 0.82-0.74 (m, 2H).

Synthesis of (6-cyclopropylpyrazolo[1,5-a]pyrimidin-2-yl)methanol

To a solution of methyl6-cyclopropylpyrazolo[1,5-a]pyrimidine-2-carboxylate (230 mg, 1.1 mmol)in dry THF (20 mL) at 0° C. was added LiAlH4 portion-wise (114 mg, 3mmol). The resulting mixture was stirred at 0° C. for 1 h. The reactionwas quenched sequentially with H₂O (0.5 mL), 15% NaOH (0.5 mL) and H₂O(1.5 mL). The resulting mixture was filtered and the filtrate wasconcentrated to get the crude product(6-cyclopropylpyrazolo[1,5-a]pyrimidin-2-yl)methanol (190 mg, 91%) as alight yellow oil which was used into next step directly withoutpurification. ESI-MS [M+H]⁺: 189.9.

Synthesis of 2-(azidomethyl)-6-cyclopropylpyrazolo[1,5-a]pyrimidine

To a solution of (6-cyclopropylpyrazolo[1,5-a]pyrimidin-2-yl)methanol(190 mg, 1 mmol) and DPPA (330 mg, 1.2 mmol) in dry THF (20 mL) stirringat 0° C. was added DBU (182 mg, 1.2 mmol). The resulting mixture wasstirred at RT overnight. The reaction mixture was concentrated to get aresidue which was purified by flash column chromatography (0-5% MeOH inDCM) to get the product2-(azidomethyl)-6-cyclopropylpyrazolo[1,5-a]pyrimidine (127 mg, 58%) asa light yellow oil. ESI-MS [M+H]⁺: 214.8.

Synthesis of Ethyl1-((6-cyclopropylpyrazolo[1,5-a]pyrimidin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate

To a solution of 2-(azidomethyl)-6-cyclopropylpyrazolo[1,5-a]pyrimidine(145 mg, 0.68 mmol) in t-BuOH (3 mL) and H₂O (3 mL) was addedsequentially of CuSO₄-5H₂O (34 mg, 0.136 mmol), sodium ascorbate (40 mg,0.204 mmol) and ethyl propiolate (133 mg, 1.36 mmol). The resultingmixture was stirred at RT for 15 h. The reaction mixture wasconcentrated to get the crude product which was purified by flash columnchromatography (0-3% MeOH in DCM) to get the product ethyl1-((6-cyclopropylpyrazolo[1,5-a]pyrimidin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(120 mg, 56%) as a light yellow oil. ESI-MS [M+H]⁺: 313.2

Synthesis of1-((6-cyclopropylpyrazolo[1,5-a]pyrimidin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicAcid

To a solution of ethyl1-((6-cyclopropylpyrazolo[1,5-a]pyrimidin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(120 mg, 0.38 mmol) in THF (5 mL) was added a solution of NaOH (38 mg,0.95 mmol) in H₂O (5 mL). The mixture was stirred at RT for 2 h. Thevolatile was removed in vacuo and the aqueous phase was acidified to pH4-5 with 2N HCl, then concentrated in vacuo to give1-((6-cyclopropylpyrazolo[1,5-a]pyrimidin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (160 mg, crude) as a light yellow solid which was used into nextstep directly. ESI-MS [M+H]⁺: 285.1

Synthesis ofN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylpyrazolo[1,5-a]pyrimidin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(I-209)

To a mixture of1-((6-cyclopropylpyrazolo[1,5-a]pyrimidin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (160 mg, crude), HATU (159 mg, 0.42 mmol) and DIPEA (147 mg, 1.14mmol) in DMF (3 mL) was added(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride(89 mg, 0.38 mmol). The resulting mixture was stirred at RT for 15 h.The reaction mixture was concentrated to get a residue which waspurified by flash column chromatography (0-8% MeOH in DCM) and thenprep-TLC (DCM/MeOH=15/1) to getN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylpyrazolo[1,5-a]pyrimidin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(70 mg, 39% over 2 steps) as an off-white solid. ESI-MS [M+H]⁺: 465.9.Purity: 96.42 (214 nm), 99.68 (254 nm). ¹H NMR (400 MHz, DMSO-d₆) δ 8.85(s, 1H), 8.73 (t, J=5.4 Hz, 1H), 8.63 (s, 1H), 8.45 (s, 2H), 8.21 (d,J=7.4 Hz, 1H), 6.77 (t, J=6.9 Hz, 1H), 6.68 (s, 1H), 5.87 (s, 2H), 4.71(d, J=5.4 Hz, 2H), 2.05-1.96 (m, 1H), 1.01-0.93 (m, 2H), 0.87-0.81 (m,2H).

Example 210

Synthesis of tert-butyl1-((8-(bromomethyl)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate

To a solution of tert-butyl1-((6-cyclopropyl-8-(hydroxymethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(1 g, 2.7 mmol) and PPh₃ (855 mg, 3.25 mmol) in DCM (50 mL) was addedCBr₄ (1.06 g, 3.25 mmol) at 0° C. The reaction was stirred at RT for 12h. H₂O (100 mL) was added to the reaction, extracted with DCM (100mL×3). The combined organic layers were washed with brine, dried overNa₂SO₄, concentrated in vacuo to give crude, which was purified withsilica gel (EA/PE=1/2) to give the tert-butyl1-((8-(bromomethyl)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylateas a yellow solid. (1.0 g, 86%). ESI-MS [M+H]⁺: 432.3.

Synthesis of tert-butyl1-((6-cyclopropyl-1-(2-methoxy-2-oxoethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate

A mixture of tert-butyl1-((8-(bromomethyl)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(1 g, 2.32 mmol), Pd(dppf)C₂ (170 mg, 0.23 mmol) and TEA (703 mg, 6.96mmol) in MeOH (75 mL) was stirred at 65° C. under CO atmosphere for 8 h.The reaction was concentrated in vacuo to give the crude, which waspurified with silica gel (DCM/MeOH=25/1) to give the tert-butyl1-((6-cyclopropyl-8-(2-methoxy-2-oxoethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylateas a yellow solid. (850 mg, 89%). ESI-MS [M+H]⁺: 412.2.

Synthesis of tert-butyl1-((6-cyclopropyl-8-(2-methoxy-2-oxoethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate

A solution of tert-butyl1-((6-cyclopropyl-8-(2-methoxy-2-oxoethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(850 mg, 2.06 mmol), NH₂NH₂—H₂O (20 mL) and MeOH (60 mL) in a sealedtube and stirred at 40° C. for 4 h. The reaction was concentrated invacuo to give the crude, which was purified with silica gel(DCM/MeOH=15/1) to give the tert-butyl1-((6-cyclopropyl-8-(2-hydrazinyl-2-oxoethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylateas a yellow solid, which was used into next step without furtherpurification. (450 mg, 53%). ESI-MS [M+H]⁺: 412.2.

Synthesis of tert-butyl1-((6-cyclopropyl-8-(2-(2-(2-ethoxy-2-oxoacetyl)hydrazinyl)-2-oxoethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate

To a solution of tert-butyl1-((6-cyclopropyl-8-(2-hydrazinyl-2-oxoethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(450 mg, 1.1 mmol) and DIPEA (426 mg, 3.3 mmol) in DCM (40 mL) was addedethyl 2-chloro-2-oxoacetate (538 mg, 3.96 mmol) at 0° C. The reactionwas allowed to warm to RT and stirred for 4 h. The reaction was quenchedwith H₂O (70 mL), extracted with DCM (70 mL×3). The combined organiclayers were washed with brine, dried over Na₂SO₄, concentrated in vacuoto give the crude, which was purified with silica gel (DCM/MeOH=30/1) togive the tert-butyl1-((6-cyclopropyl-8-(2-(2-(2-ethoxy-2-oxoacetyl)hydrazinyl)-2-oxoethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylateas a yellow solid. (380 mg, 68%). ESI-MS [M+H]⁺: 512.2.

Synthesis of Ethyl5-((2-((4-(tert-butoxycarbonyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)methyl)-1,3,4-oxadiazole-2-carboxylate

solution of tert-butyl1-((6-cyclopropyl-8-(2-(2-(2-ethoxy-2-oxoacetyl)hydrazinyl)-2-oxoethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(380 mg. 0.74 mmol), tosyl chloride (211 mg, 1.11 mmol) and TEA (187 mg,1.85 mmol) in DCM (30 mL) was stirred at RT for 12 h. The reaction wasconcentrated in vacuo to give the crude, which was purified withPrep-TLC (DCM/MeOH=15/1) to give the ethyl5-((2-((4-(tert-butoxycarbonyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)methyl)-1,3,4-oxadiazole-2-carboxylateas a white solid. (300 mg, 82%). ESI-MS [M+H]⁺: 494.2

Synthesis of1-((6-cyclopropyl-8-((5-(ethoxycarbonyl)-1,3,4-oxadiazol-2-yl)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicAcid

A solution of ethyl5-((2-((4-(tert-butoxycarbonyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)methyl)-1,3,4-oxadiazole-2-carboxylate(300 mg, 0.61 mmol) in TFA/DCM (5 mL/15 mL) was stirred at RT for 14 h.The reaction was concentrated in vacuo to give the1-((6-cyclopropyl-8-((5-(ethoxycarbonyl)-1,3,4-oxadiazol-2-yl)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid as a yellow solid, which was used into next step without furtherpurification. (290 mg crude). ESI-MS [M+H]⁺: 438.2

Synthesis of Ethyl5-((2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)methyl)-1,3,4-oxadiazole-2-carboxylate(I-210a)

To a solution of1-((6-cyclopropyl-8-((5-(ethoxycarbonyl)-1,3,4-oxadiazol-2-yl)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (290 mg, crude from previous step) and in DMF (20 mL) was addedHATU (342 mg, 0.9 mmol) and DIPEA (232 mg, 1.8 mmol). The resultingmixture was stirred at RT for 1 h. Then(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride(173 mg, 0.73 mmol) was added thereto. The reaction mixture was stirredat RT for 12 h. H₂O (50 mL) was added, and the reaction was extractedwith EtOAc (80 mL×3). The combined organic layers were washed withbrine, dried over Na₂SO₄, concentrated in vacuo to give the crude, whichwas purified with Prep-TLC (DCM/MeoH=10/1) to give the ethyl5-((2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)methyl)-1,3,4-oxadiazole-2-carboxylateas a white solid. (100 mg, 26% over 2 steps). ESI-MS [M+H]⁺: 619.2.Purity: 98.86 (214 nm), 98.65 (254 nm). ¹H NMR (400 MHz, DMSO-d₆) δ 8.68(t, J=5.5 Hz, 1H), 8.49 (s, 1H), 8.44 (d, J=2.4 Hz, 1H), 8.33 (d, J=1.1Hz, 1H), 8.21 (d, J=7.4 Hz, 1H), 7.83 (s, 1H), 7.06 (s, 1H), 6.83-6.70(m, 1H), 5.71 (s, 2H), 4.70 (d, J=5.5 Hz, 2H), 4.58 (s, 2H), 4.38 (q,J=7.1 Hz, 2H), 1.96-1.90 (m, 1H), 1.31 (t, J=7.1 Hz, 3H), 0.95-0.90 (m,2H), 0.69-0.65 (m, 2H).

Synthesis of1-((8-((1,3,4-oxadiazol-2-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(I-210a)

To a solution of ethyl5-((2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)methyl)-1,3,4-oxadiazole-2-carboxylate(65 mg, 0.105 mmol) in THF/H₂O (5 mL/5 mL) was added LiOH.H₂O (18 mg,0.42 mmol). The resulting mixture was stirred at RT for 3 h. Thereaction was concentrated in vacuo to give the crude, which wasre-dissolved in 1N HCl (5 mL) and stirred for another 1 h. The reactionwas concentrated in vacuo to give the crude, which was purified withPrep-HPLC to give the1-((8-((1,3,4-oxadiazol-2-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-1,2,3-triazole-4-carboxamideas a white solid (21 mg, 37%). ESI-MS [M+H]⁺: 547.2. Purity: 94.34 (214nm), 96.58 (254 nm). ¹H NMR (400 MHz, DMSO-d₆) δ 9.16 (d, J=2.4 Hz, 1H),8.75 (t, J=5.3 Hz, 1H), 8.59 (d, J=6.9 Hz, 1H), 8.53-8.47 (m, 2H), 8.21(d, J=7.4 Hz, 1H), 8.02 (s, 1H), 7.33-7.27 (m, 2H), 7.18 (d, J=12.9 Hz,1H), 7.03 (s, 1H), 6.79-6.76 (m, 1H), 5.83 (s, 2H), 4.71 (d, J=5.5 Hz,2H), 4.57 (s, 2H), 2.05-1.93 (m, 1H), 1.03-0.95 (m, 1H), 0.76-0.68 (m,2H).

Example 211

Synthesis of Ethyl 5-cyclopropyl-1H-indole-2-carboxylate

A solution of ethyl 5-bromo-1H-indole-2-carboxylate (2.68 g, 10 mmol),cyclopropylboronic acid (1.29 g, 15 mmol), Pd(OAc)₂ (113 mg, 0.5 mmol),K₃PO₄ (4.25 g, 20 mmol) and SPhos (205 mg, 0.5 mmol) in toluene (20 mL)and H₂O (4 mL) was stirred at 80° C. under N₂ overnight. Toluene wasconcentrated and H₂O was added (30 mL), extracted by EtOAc (100 mL*3).The combined organic layers were concentrated and purified by silica gelchromatography (EA/PE=1:8) to give ethyl5-cyclopropyl-1H-indole-2-carboxylate (1.6 g, yield: 70%) as a yellowsolid. ESI-MS [M+H]⁺: 230.2.

Synthesis of Ethyl 5-cyclopropyl-3-iodo-1H-indole-2-carboxylate

A solution of ethyl 5-cyclopropyl-1H-indole-2-carboxylate (1.55 g, 6.76mmol), I₂ (1.72 g, 6.76 mmol) and KOH (1.52 g, 27.04 mmol) in DMF (10mL) was stirred at RT for 3 h. The mixture was quenched by adding asaturated thiosulfate solution. Water (50 mL) was added, extracted byEtOAc (100 mL*3). The combined organic layers were concentrated to givecrude ethyl 5-cyclopropyl-3-iodo-1H-indole-2-carboxylate (2.33 g, yield:97%) as a yellow solid. ESI-MS [M+H]⁺: 356.0.

Synthesis of Ethyl5-cyclopropyl-3-(trifluoromethyl)-1H-indole-2-carboxylate

A mixture of ethyl 5-cyclopropyl-3-iodo-1H-indole-2-carboxylate (1.06 g,3 mmol), diphenyl(trifluoromethyl)sulfonium trifluoromethanesulfonate(2.43 g, 6 mmol) and copper powder (572 mg, 9 mmol) in DMF (20 mL) wasstirred at 60° C. overnight. The mixture was filtered, Water (50 mL) wasadded to the filtrate and extracted by EtOAc (100 mL×3). The combinedorganic layers were concentrated and purified by silica gelchromatography (EA/PE=1:5) to give ethyl5-cyclopropyl-3-(trifluoromethyl)-1H-indole-2-carboxylate (350 mg,yield: 39%) as a yellow oil. ESI-MS [M+H]⁺: 298.1.

Synthesis of Ethyl5-cyclopropyl-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-2-carboxylate

To a solution of ethyl5-cyclopropyl-3-(trifluoromethyl)-1H-indole-2-carboxylate (330 mg, 1.11mmol) in THF (10 mL) added NaH (110 mg, 60 wt %, 1.67 mmol) at RTslowly. The mixture was stirred at RT for 10 minutes. Then(2-(chloromethoxy)ethyl)trimethylsilane (222 mg, 1.33 mmol) was added.After the mixture was stirred at RT for 3 h, H₂O (50 mL) was added andextracted by EtOAc (100 mL×3). The combined organic layers wereconcentrated to give crude ethyl5-cyclopropyl-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-2-carboxylate(460 mg, crude) as a yellow solid, which was used into the next stepwithout further purification. ESI-MS [M+Na]⁺: 450.3

Synthesis of(5-cyclopropyl-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-2-yl)methanol

To a solution of ethyl5-cyclopropyl-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-2-carboxylate(460 mg, 1.11 mmol) in THF (15 mL) added LiAlH₄ (63 mg, 1.67 mmol)slowly at 0° C. The mixture was stirred at RT for 3 h. After that,NaSO₄.10H₂O was added to quench the reaction and the mixture was stirredat RT for another 0.5 h. The mixture was filtered, and the filtrate wasconcentrated and purified by silica gel chromatography (PE:EA=8:1) togive(5-cyclopropyl-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-2-yl)methanol(207 mg, 48%) as a yellow solid. ESI-MS [M+H]⁺: 386.1.

Synthesis of2-(chloromethyl)-5-cyclopropyl-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole

A mixture of(5-cyclopropyl-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-2-yl)methanol(207 mg, 0.54 mmol), MsCl (92 mg, 0.81 mmol) and Et₃N (163 mg, 1.6 mmol)in DCM (10 mL) was stirred at RT overnight. Water was added andextracted with EtOAc, combined organic layers were concentrated to givethe crude product (230 mg, crude) which was used into next step withoutfurther purification.

Synthesis of2-(azidomethyl)-5-cyclopropyl-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole

A mixture of2-(chloromethyl)-5-cyclopropyl-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole(230 mg, crude from last step) and NaN₃ (72 mg, 1.2 mmol) in DMF (5 mL)was stirred at RT for 3 h. Water (20 mL) was added and extracted byEtOAc (30 mL×3). The organic layers was concentrated to give2-(azidomethyl)-5-cyclopropyl-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole(256 mg, crude) as a yellow oil.

Synthesis of Ethyl1-((5-cyclopropyl-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate

A solution of2-(azidomethyl)-5-cyclopropyl-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole(256 mg, crude), ethyl propiolate (123 mg, 1.25 mmol) sodium ascorbate(109 mg, 0.62 mmol) and CuSO₄ (49 mg, 0.31 mmol) in tert-BuoH (10 mL)and H₂O (10 mL) was stirred at RT overnight. Water (30 mL) was added andextracted with EtOAc (30 mL×3). The combined organic layers wereconcentrated to give ethyl1-((5-cyclopropyl-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(250 mg, crude) as a yellow solid, which was used into next step withoutpurification.

Synthesis of1-((5-cyclopropyl-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicAcid

A solution of ethyl1-((5-cyclopropyl-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(125 mg, crude from last step) and LiOH.H₂O (22 mg, 0.5 mmol) in THF (4mL), EtOH (2 mL) and H₂O (1 mL) was stirred at 50° C. for 2 h. Themixture was concentrated and H₂O (3 mL) was added, pH value was adjustedto 3 by adding 1 M HCl. Concentrated to afford1-((5-cyclopropyl-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid as a yellow solid (150 mg, crude), which was used into the nextstep without purification. ESI-MS [M+Na]⁺: 503.2.

Synthesis ofN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((5-cyclopropyl-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide

A mixture of crude1-((5-cyclopropyl-3-(trifluormethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (150 mg, crude from last step),(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride(59 mg, 0.25 mmol), HOBT (67 mg, 0.5 mmol), EDCI (96 mg, 0.5 mmol) andDIPEA (162 mg, 1.25 mmol) in DMF (5 mL) was stirred at RT overnight.Water (20 mL) was added and extracted by EtOAc (30 mL×3). The combinedorganic layers were concentrated to give crude product, which was usedinto the next step without further purification. ESI-MS [M+H]⁺: 662.1.

Synthesis ofN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((5-cyclopropyl-3-(trifluoromethyl)-1H-indol-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(I-211)

A solution ofN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((5-cyclopropyl-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(crude from above step) in TFA/DCM (v:v=1:1, 4 mL) was stirred at RT for3 h. The solvent was removed by evaporation and the residue was dilutedwith H₂O. The aqueous layer was adjust to pH=9 with saturated Na₂CO₃solution and extracted by EtOAc (50 mL*3). The combined organic layerswere concentrated and purified by Prep-HPLC to giveN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((5-cyclopropyl-3-(trifluoromethyl)-1H-indol-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(7.5 mg) as a white solid. ESI-MS [M+H]⁺: 532.1. Purity: 99.65 (214 nm),100.00 (254 nm). ¹H NMR (400 MHz, DMSO-d₆) δ 12.10 (s, 1H), 8.75 (t,J=5.4 Hz, 1H), 8.55 (s, 1H), 8.43 (d, J=2.3 Hz, 1H), 8.20 (d, J=7.4 Hz,1H), 7.37 (d, J=8.5 Hz, 1H), 7.30 (s, 1H), 6.97 (dd, J=8.6, 1.5 Hz, 1H),6.77-6.74 (m, 1H), 5.89 (s, 2H), 4.69 (d, J=5.5 Hz, 2H), 2.05-1.99 (m,1H), 0.93-0.90 (m, 2H), 0.65-0.61 (m, 2H).

Example 212

Synthesis of tert-butyl2-((2-amino-5-chloropyridin-3-yl)oxy)-2-methylpropanoate

To a mixture of 2-amino-5-chloropyridin-3-ol (2.9 g, 20 mmol) and Cs₂CO₃(9.8 g, 60 mmol) in MeCN (50 mL) was added tert-butyl2-bromo-2-methylpropanoate (5.4 g, 24 mmol). The mixture was stirred atRT for 16 h. Water (300 mL) was added to the reaction, extracted withEtOAc (200 mL×3). The combined organic phase was washed with brine,dried over Na₂SO₄, filtrated and concentrated to give tert-butyl2-((2-amino-5-chloropyridin-3-yl)oxy)-2-methylpropanoate (2.3 g, yield:40%) as a yellow oil, which was used into next step without furtherpurification. ESI-MS[M+H]⁺: 287.1.

Synthesis of tert-butyl2-((6-chloro-2-(chloromethyl)imidazo[1,2-a]pyridin-8-yl)oxy)-2-methylpropanoate

A mixture of tert-butyl2-((2-amino-5-chloropyridin-3-yl)oxy)-2-methylpropanoate (2.3 g, 8 mmol)and 1,3-dichloropropan-2-one (4.1 g, 32 mmol) in DMF (25 mL) was stirredat 90° C. for 3 h. After cooled, the reaction was quenched withsaturated aqueous NaHCO₃ (100 mL), extracted with EtOAc (200 mL×3). Thecombined organic phase was washed with brine, dried over Na₂SO₄,filtrated and concentrated. The residue was purified by silica gelchromatography (PE/EA=5/1 to 2/1) to give tert-butyl2-((6-chloro-2-(chloromethyl)imidazo[1,2-a]pyridin-8-yl)oxy)-2-methylpropanoate(1.1 g, yield: 38%) as a yellow oil. ESI-MS [M+H]⁺: 359.1.

Synthesis of tert-butyl2-((2-(azidomethyl)-6-chloroimidazo[1,2-a]pyridin-8-yl)oxy)-2-methylpropanoate

To a mixture of tert-butyl2-((6-chloro-2-(chloromethyl)imidazo[1,2-a]pyridin-8-yl)oxy)-2-methylpropanoate(1.1 g, 3.1 mmol) in DMF (10 mL) was added NaN₃ (300 mg, 4.6 mmol). Themixture was stirred at RT for 2 h. Water (50 mL) was added to thereaction, and extracted with EtOAc (50 mL×3). The combined organic phasewas washed with brine, dried over Na₂SO₄, filtrated and concentrated togive tert-butyl2-((2-(azidomethyl)-6-chloroimidazo[1,2-a]pyridin-8-yl)oxy)-2-methylpropanoate(1.1 g, yield: 96%) as a yellow oil, which was used into next stepwithout further purification. ESI-MS [M+H]⁺: 366.1.

Synthesis of benzyl1-((8-((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)-6-chloroimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate

To a mixture of tert-butyl2-((2-(azidomethyl)-6-chloroimidazo[1,2-a]pyridin-8-yl)oxy)-2-methylpropanoate(1.1 g, 3.0 mmol), CuSO₄ (67 mg, 0.42 mmol) and sodium ascorbate (83 mg,0.42 mmol) in t-BuOH/H₂O (15 mL/15 mL) was added benzyl propiolate (577mg, 3.6 mmol). The mixture was stirred at RT for 2 h. Water (50 mL) wasadded to the reaction and extracted with EtOAc (50 mL×3). The combinedorganic phase was washed with brine, dried over Na₂SO₄, filtrated andconcentrated to give crude, which was triturated with PE/EA (20 mL/20mL) to give benzyl1-((8-((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)-6-chloroimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(1.1 g, yield: 68%) as a blue solid. ESI-MS [M+H]⁺: 526.2.

Synthesis of benzyl1-((8-((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate

To a mixture of benzyl1-((8-((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)-6-chloroimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(526 mg, 1 mmol), cyclopropylboronic acid (180 mg, 2 mmol) and K₃PO₄(850 mg, 4 mmol) in toluene/H₂O (10 mL/1 mL) was added Pd(OAc)₂ (44 mg,0.2 mmol) and SPhos (82 mg, 0.2 mmo). The mixture was stirred at 90° C.for 16 h. Water (50 mL) was added to the reaction, and extracted withEtOAc (50 mL×3). The combined organic phase was washed with brine, driedover Na₂SO₄, filtrated and concentrated to give the residue, which waspurified by silica gel chromatography (DCM/MeOH=50/1 to 20/1) to givebenzyl1-((8-((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(300 mg, yield: 56%) as a yellow solid. ESI-MS [M+H]⁺: 532.2.

Synthesis of1-((8-((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicAcid

To a mixture of benzyl1-((8-((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(300 mg, 0.56 mmol) in EtOAc/MeOH (30 mL/10 mL) was added Pd(OH)₂ (60mg). The mixture was stirred at RT for 3 h under H₂ atmosphere. Thereaction was filtrated and washed with MeOH (100 mL). The filtrate wasconcentrated to give1-((8-((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (250 mg, yield: 100%) as a yellow oil, which was used into nextstep without further purification. ESI-MS [M+H]⁺: 442.1.

Synthesis of tert-butyl2-((2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)oxy)-2-methylpropanoate

To a mixture of1-((8-((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (250 mg, 0.56 mmol),(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride(200 mg, 0.85 mmol) and DIPEA (371 mg, 2.85 mmol) in DMF (5 mL) wasadded HOBT (154 mg, 1.14 mmol) and EDC (210 mg, 1.14 mmol). The mixturewas stirred at RT for 16 h. Water (50 mL) was added to the reaction, andextracted with EtOAc (50 mL×3). The combined organic phase was washedwith brine, dried over Na₂SO₄, filtrated and concentrated to give theresidue, which was purified by Prep-TLC (DCM/MeOH=10/1) to givetert-butyl2-((2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)oxy)-2-methylpropanoate(160 mg, yield: 45%) as a white solid. ESI-MS [M+H]⁺: 623.1.

Synthesis of2-((2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)oxy)-2-methylpropanoicacid (I-212)

To a mixture of tert-butyl2-((2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)oxy)-2-methylpropanoate(80 mg, 0.13 mmol) in DCM (5 mL) was added TFA (2 mL). The mixture wasstirred at RT for 2 h. The reaction was concentrated to give theresidue. The pH of the residue was adjusted to 5 by saturated aqueousNa₂CO₃, and the white solid was precipitated. The mixture was filtered,the cake washed with DCM (20 mL) and dried to give2-((2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)oxy)-2-methylpropanoicacid (50 mg, yield: 67%) as a white solid. ESI-MS [M+H]⁺: 567.1. Purity:99.4 (214 nm), 100.0 (254 nm). ¹H NMR (400 MHz, DMSO-d₆) δ 13.34 (s,1H), 8.70 (t, J=5.4 Hz, 1H), 8.54 (s, 1H), 8.44 (d, J=2.4 Hz, 1H), 8.20(d, J=7.4 Hz, 1H), 8.01 (s, 1H), 7.80 (s, 1H), 6.80-6.71 (m, 1H), 6.12(s, 1H), 5.71 (s, 2H), 4.70 (d, J=5.5 Hz, 2H), 1.93-1.83 (m, 1H), 1.59(s, 6H), 1.01-0.86 (m, 2H), 0.65-0.49 (m, 2H).

Example 213

Synthesis of Methyl1-((6-cyclopropyl-8-(1-hydroxyethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate

To a solution of benzyl1-((8-acetyl-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(500 mg, 1.2 mmol) in MeOH (10 mL) was added NaBH₄ (137 mg, 3.6 mmol) at0° C. The reaction mixture was stirred at RT for 2 h. The reaction wasquenched with H₂O (30 mL) and extracted by EtOAc (30 mL×3). Then thecombined organic layers were washed with brine, dried over Na₂SO₄,concentrated to give the crude, which was purified by flash silica gelchromatography (PE/EA=1/1) to give methyl1-((6-cyclopropyl-8-(1-hydroxyethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(300 mg, yield: 73%) as a white solid. ESI-MS [M+H]⁺: 342.1.

Synthesis of Methyl1-((6-cyclopropyl-8-(1-fluoroethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate

To a solution of methyl1-((6-cyclopropyl-8-(1-hydroxyethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(300 mg, 0.88 mmol) in DCM (10 mL) was added DAST (213 mg, 1.32 mmol) at0° C. The mixture was stirred at 0° C. for another 2 h. The reaction wasquenched by H₂O (30 mL), and extracted by EtOAc (30 mL×3). Then thecombined organic layers were washed with brine, dried over Na₂SO₄,concentrated to give the crude, which was purified by flash silica gelchromatography (PE/EA=1/1) to give methyl1-((6-cyclopropyl-8-(1-fluoroethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(80 mg, yield: 26.6%) as a red solid. ESI-MS [M+H]⁺: 344.1

Synthesis of1-((6-cyclopropyl-8-(1-fluoroethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicAcid

To a solution of methyl1-((6-cyclopropyl-8-(1-fluoroethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(80 mg, 0.233 mmol) in EtOH/THF/H₂O (2 mL/2 mL/1 mL) was added LiOH.H₂O(19.1 mg, 0.466 mmol) at RT. The mixture was stirred for 2 h. The pH ofthe reaction was adjusted to 5 by HCl (1N), and then freeze-dried togive1-((6-cyclopropyl-8-(1-fluoroethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (100 mg, crude) as a white solid, which was used into next stepwithout further purification. ESI-MS [M+H]⁺: 330.1.

Synthesis ofN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(1-fluoroethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(I-213)

To a solution of1-((6-cyclopropyl-8-(1-fluoroethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (100 mg, crude from previous step),(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride(72 mg, 0.3 mmol), HATU (171 mg, 0.45 mmol) in DMF (5 mL) was addedDIPEA (90 mg, 0.7 mmol). The resulting reaction was stirred at RT for 14h. Water (50 mL) was added to the reaction, extracted with EtOAc (50mL×3). The combined organic layers were washed with brine, dried overNa₂SO₄, concentrated to give the crude, which was purified by Prep-TLC(DCM/MeOH=10/1) to giveN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(1-fluoroethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(14.6 mg, yield: 12% over 2 steps) as a yellow solid. ESI-MS [M+H]⁺:511.1. Purity: 98.8 (214 nm), 100.00 (254 nm). ¹H NMR (400 MHz, DMSO-d₆)8.72 (t, J=5.4 Hz, 1H), 8.56 (s, 1H), 8.44 (d, J=2.4 Hz, 1H), 8.33 (s,1H), 8.20 (d, J=7.4 Hz, 1H), 7.85 (s, 1H), 7.07 (s, 1H), 6.78-6.74 (m,1H), 6.17-5.99 (m, 1H), 5.76 (s, 2H), 4.70 (d, J=5.5 Hz, 2H), 2.00-1.93(m, 1H), 1.71 (dd, J=24.4, 6.4 Hz, 3H), 0.96-0.91 (m, 2H), 0.73-0.65 (m,2H).

Example 214

Synthesis of 5-cyclopropylpyridin-2-amine

A mixture of 5-bromopyridin-2-amine (5 g, 29 mmol), cyclopropylboronicacid (4.97 g, 58 mmol), Pd(OAc)₂ (0.65 g, 2.9 mol), SPhos (2.37 g, 5.8mol) and K₃PO₄ (18.38 g, 87 mol) in toluene/H₂O (150 mL/15 mL) wasstirred at 100° C. for 16 h. The reaction mixture was filtered throughcelite, washed with EtOAc (300 mL). The filtrate was concentrated togive the crude, which was purified by flash (ethyl acetate) to give5-cyclopropylpyridin-2-amine (3.8 g, 97% yield) as a yellow oil. ESI-MS[M+H]⁺: 135.2.

Synthesis of 3-bromo-5-cyclopropylpyridin-2-amine

To a solution of 5-cyclopropylpyridin-2-amine (3.7 g, 28 mol) in MeCN(100 mL) was added NBS (4.9 g, 0.028 mol) at 0° C. The resultingreaction was stirred at 0° C. for 2 h. The reaction was concentrated togive the crude, which was purified by silica gel column chromatography(PE/EA=1/1) to give 3-bromo-5-cyclopropylpyridin-2-amine (4.5 g, 75%yield) as a yellow solid. ESI-MS [M+H]⁺: 213.0

Synthesis of8-bromo-2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine

The mixture of 3-bromo-5-cyclopropylpyridin-2-amine (4.4 g, 20 mol),1,3-dichloropropan-2-one (10.5 g, 80 mol) in EtOH (200 mL) was stirredat 80° C. for 16 h. The reaction was concentrated to give the residue,which was diluted with ethyl acetate (100 mL), washed by saturatedaqueous NaHCO₃ (50 mL), H₂O (50 mL) and brine (50 mL), dried overNa₂SO₄, concentrated to give the crude, which was purified by silica gelcolumn chromatography (EA/PE=1/1) to give8-bromo-2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine (2.2 g, 37%yield). ESI-MS [M+H]⁺: 285.0.

Synthesis of Methyl1-((8-bromo-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate

The mixture of8-bromo-2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine (2.2 g, 7.7mmol), methyl 1H-pyrazole-4-carboxylate (0.97 g, 7.7 mmol), and Cs₂CO₃(5 g, 15.4 mmol) in DMF (30 mL) was stirred at 50° C. for 3 h. H₂O (150mL) was added to the reaction, extracted with ethyl acetate (200 mL×3).The combined organic layers were washed with brine, dried over Na₂SO₄,concentrated to give the crude, which was purified by silica gel columnchromatography (PE/EA=1/2) to give methyl1-((8-bromo-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate(2.4 g, 83%) as a yellow solid. ESI-MS [M+H]⁺: 375.1. ¹H NMR (400 MHz,DMSO-d₆) δ 8.43 (d, J=0.5 Hz, 1H), 8.38 (d, J=1.0 Hz, 1H), 7.89 (d,J=0.6 Hz, 1H), 7.85 (s, 1H), 7.39 (d, J=1.5 Hz, 1H), 5.49 (s, 2H), 3.74(s, 3H), 1.97-1.86 (m, 1H), 0.94-0.90 (m, 2H), 0.78-0.66 (m, 2H).

Synthesis of Methyl1-((8-(2-tert-butoxy-2-oxoethyl)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate

A mixture of methyl1-((8-bromo-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate(1.2 g, 3.2 mmol), (2-tert-butoxy-2-oxoethyl)zinc(II) bromide (4.2 g, 16mmol), Pd₂(dba)₃ (2.9 g, 3.2 mmol), QPhos (455 mg, 0.64 mmol) in THF (60mL) was stirred at 65° C. for 16 h. The reaction was concentrated togive the crude, which was purified by silica gel column chromatography(DCM/EA=4/1) to give methyl1-((8-(2-tert-butoxy-2-oxoethyl)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate(540 mg, 42% yield) as a yellow solid. ESI-MS [M+H]⁺: 411.2

Synthesis of2-(6-cyclopropyl-2-((4-(methoxycarbonyl)-1H-pyrazol-1-yl)methyl)imidazo[1,2-a]pyridin-8-yl)aceticAcid

A mixture of methyl1-((8-(2-tert-butoxy-2-oxoethyl)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate(540 mg, 1.3 mmol) in DCM (40 mL) was added TFA (10 mL) dropwise. Theresulting mixture was stirred at RT for 1 h. The reaction wasconcentrated to give the crude, which was purified by silica gel columnchromatography (DCM/MeOH=4/1) to give2-(6-cyclopropyl-2-((4-(methoxycarbonyl)-1H-pyrazol-1-yl)methyl)imidazo[1,2-a]pyridin-8-yl)aceticacid (340 mg, 73% yield) as a yellow solid. ESI-MS [M+H]⁺: 355.1.

Synthesis of Methyl1-((8-(2-(2-(tert-butoxycarbonyl)hydrazinyl)-2-oxoethyl)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate

A mixture of2-(6-cyclopropyl-2-((4-(methoxycarbonyl)-1H-pyrazol-1-yl)methyl)imidazo[1,2-a]pyridin-8-yl)aceticacid (310 mg, 0.88 mmol), BocNHNH₂ (232 mg, 1.76 mmol), HATU (401 mg,1.056 mmol) and DIPEA (454 mg, 3.52 mmol) in DMF (6 mL) was stirred atRT for 16 h. Water (30 mL) was added to the reaction, extracted withethyl acetate (50 mL×3). The combined organic layers were washed withbrine (20 mL), dried over Na₂SO₄, concentrated to give the crude, whichwas purified by silica gel column chromatography (DCM/MeOH=15/1) to givemethyl1-((8-(2-(2-(tert-butoxycarbonyl)hydrazinyl)-2-oxoethyl)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate(300 mg, 73% yield) as a yellow solid. ESI-MS [M+H]⁺: 469.2

Synthesis of Methyl1-((6-cyclopropyl-8-(2-hydrazinyl-2-oxoethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate

A mixture of methyl1-((8-(2-(2-(tert-butoxycarbonyl)hydrazinyl)-2-oxoethyl)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate(300 mg, 0.64 mmol) in DCM (30 mL) was added TFA (3 mL) dropwise. Theresulting mixture was stirred at RT for 1 h. The reaction mixture wasconcentrated, diluted with DCM (50 mL), washed by saturated aqueousNaHCO₃ (30 mL), H₂O (30 mL), dried over Na₂SO₄, then concentrated togive methyl1-((6-cyclopropyl-8-(2-hydrazinyl-2-oxoethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylateas a yellow oil, which was used into next step without furtherpurification. ESI-MS [M+H]⁺: 369.0

Synthesis of Methyl1-((6-cyclopropyl-8-(2-hydrazinyl-2-oxoethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate

A mixture of methyl1-((6-cyclopropyl-8-(2-hydrazinyl-2-oxoethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate(150 mg, crude from last step), ethyl orthoformate (2.8 mL), and AcOH(1.4 mL) in toluene (7 mL) was stirred at 100° C. for 10 h. The reactionwas concentrated to give the crude, which was purified by silica gelcolumn chromatography (DCM/MeOH=90/10) to give methyl1-((6-cyclopropyl-8-(2-hydrazinyl-2-oxoethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate(40 mg, 16% yield over 2 steps) as yellow oil. ESI-MS [M+H]⁺: 379.2

Synthesis of1-((8-((1,3,4-oxadiazol-2-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylicAcid

A mixture of methyl1-((8-((1,3,4-oxadiazol-2-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate(40 mg, 0.1 mmol), LiOH (18 mg, 0.4 mmol) in THF/H₂O (4 mL/2 mL) wasstirred at 0° C. for 16 h. The reaction was concentrated andfreeze-dried to give1-((8-((1,3,4-oxadiazol-2-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylicacid (60 mg, crude) as a yellow solid, which was used into next stepwithout further purification. ESI-MS [M+H]⁺: 365.1

Synthesis of1-((8-((1,3,4-oxadiazol-2-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide(I-214)

A mixture of1-((8-((1,3,4-oxadiazol-2-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylicacid (60 mg, crude from last step),(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride(19 mg, 0.08 mmol), HATU (36 mg, 0.096 mmol), DIPEA (31 mg, 0.24 mmol)in DMF (3 mL) was stirred at RT for 16 h. Water (20 mL) was added to thereaction, extracted with ethyl acetate (20 mL×3). The combined organiclayers were washed by brine (10 mL), dried over Na₂SO₄, concentrated togive the crude, which was purified by Prep-HPLC (DCM/MeOH=10/1) to give1-((8-((1,3,4-oxadiazol-2-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide(10 mg, 22% yield) as a white solid. ESI-MS [M+H]⁺: 546.2. Purity:100.00% (214 nm), 100.00% (254 nm). ¹H NMR (400 MHz, DMSO-d₆) δ 9.14 (s,1H), 8.46-8.39 (m, 3H), 8.22-8.13 (m, 2H), 7.88-7.81 (m, 2H), 7.19 (s,1H), 6.79-6.75 (m, 1H), 5.45 (s, 2H), 4.63 (d, J=5.1 Hz, 2H), 4.53 (s,2H), 1.96 (s, 1H), 0.95 (d, J=8.0 Hz, 2H), 0.68 (d, J=4.5 Hz, 2H).

Example 215

Synthesis of 3-(2-amino-5-chloropyridin-3-yl)oxetan-3-ol

To the solution of 3-bromo-5-chloropyridin-2-amine (5 g, 24 mmol) in THF(100 mL) was added n-BuLi (35 mL, 2.4 M solution in hexanes, 84 mmol)dropwise at −78° C. After 5 minutes, oxetan-3-one (17 g, 240 mmol) inTHF (50 mL) was added thereto and stirred at −78° C. for 2 h. Thereaction was quenched with saturated aqueous NH₄Cl (100 mL), extractedwith ethyl acetate (100 mL×3). The combined organic layers were washedby brine (50 mL) and dried over Na₂SO₄, concentrated to give the crude,which was purified by silica gel column chromatography (DCM/MeOH=15/1)to give 3-(2-amino-5-chloropyridin-3-yl)oxetan-3-ol (2.8 g, 58% yield)as a yellow solid. ESI-MS [M+H]⁺: 201.1. ¹H NMR (400 MHz, DMSO-d₆) δ7.93 (d, J=2.5 Hz, 1H), 7.61 (d, J=2.5 Hz, 1H), 6.49 (s, 1H), 5.81 (s,2H), 4.84 (d, J=7.4 Hz, 2H), 4.72 (d, J=7.4 Hz, 2H).

Synthesis of 3-(2-amino-5-cyclopropylpyridin-3-yl)oxetan-3-ol

A mixture of 3-(2-amino-5-chloropyridin-3-yl)oxetan-3-ol (2.8 g, 14mmol), cyclopropylboronic acid (2.4 g, 28 mmol), K₃PO₄ (8.9 g, 42 mmol),SPhos (1.1 g, 2.7 mmol) and Pd(OAc)₂ (0.3 g, 1.3 mmol) in toluene/H₂O(50 mL/5 mL) was stirred at 90° C. for 16 h. The reaction mixture wasfiltered through celite, washed with EtOAc (100 mL). The filtrate wasconcentrated to give the crude, which was purified by silica gel columnchromatography (DCM/MeOH=8/1) to give3-(2-amino-5-cyclopropylpyridin-3-yl)oxetan-3-ol (2.1 g, 73% yield) as ayellow solid. ESI-MS [M+H]⁺: 207.2. ¹H NMR (400 MHz, DMSO-d₆) δ 7.75 (d,J=1.8 Hz, 1H), 7.17 (d, J=2.1 Hz, 1H), 6.34 (s, 1H), 5.34 (s, 2H), 4.85(d, J=7.1 Hz, 2H), 4.70 (d, J=7.2 Hz, 2H), 3.61 (s, 1H), 1.85-1.78 (m,1H), 0.86-0.80 (m, 2H), 0.64-0.59 (m, 2H).

Synthesis of3-(2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)oxetan-3-ol

A mixture of 3-(2-amino-5-cyclopropylpyridin-3-yl)oxetan-3-ol (2 g, 9.7mmol), 1,3-dichloropropan-2-one (3.85 g, 31 mmol) in EtOH (50 mL) wasstirred at 80° C. for 16 h. The reaction was concentrated and theresidue was diluted with ethyl acetate (50 mL), washed by saturatedaqueous NaHCO₃ (30 mL), H₂O (30 mL) and brine (30 mL), dried overNa₂SO₄, and concentrated to give the crude, which was purified by silicagel column chromatography (DCM/MeOH=8/1) to give3-(2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)oxetan-3-ol(1.2 g, 44% yield) as a yellow solid. ESI-MS [M+H]⁺: 279.1. ¹H NMR (400MHz, DMSO-d₆) δ 8.54 (s, 1H), 8.15 (s, 1H), 7.54 (s, 1H), 5.10 (d, J=6.5Hz, 2H), 4.96 (s, 2H), 4.80 (d, J=6.4 Hz, 2H), 2.07 (d, J=4.7 Hz, 1H),1.06-0.98 (m, 2H), 0.80 (d, J=5.1 Hz, 2H).

Synthesis of Methyl1-((6-cyclopropyl-8-(3-hydroxyoxetan-3-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate

A mixture of3-(2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)oxetan-3-ol(1.2 g, 4.3 mmol), methyl 1H-pyrazole-4-carboxylate (0.54 g, 4.3 mmol)and Cs₂CO₃ (2.8 g, 8.6 mmol) in DMF (10 mL) was stirred at 50° C. for 3h. The reaction mixture was filtered through celite, and the filtratewas diluted with H₂O (100 mL) and extracted with ethyl acetate (100 mL).The combined organic layers were concentrated to give the crude, whichwas purified by silica gel column chromatography (DCM/MeOH=6/1) to givemethyl1-((6-cyclopropyl-8-(3-hydroxyoxetan-3-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate(890 mg, 56% yield) as a yellow solid. ESI-MS [M+H]⁺: 369.2. ¹H NMR (400MHz, DMSO-d₆) δ 8.41 (s, 1H), 8.30 (d, J=1.2 Hz, 1H), 7.90 (s, 1H), 7.70(s, 1H), 6.45 (s, 1H), 5.50 (s, 2H), 5.24 (d, J=6.5 Hz, 2H), 4.66 (d,J=6.5 Hz, 2H), 3.74 (s, 3H), 1.94 (td, J=8.4, 4.2 Hz, 1H), 0.97-0.89 (m,2H), 0.72-0.65 (m, 2H).

Synthesis of Methyl1-((6-cyclopropyl-1-(3-(methylthiocarbonothioyloxy)oxetan-3-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate

To the mixture of methyl1-((6-cyclopropyl-8-(3-hydroxyoxetan-3-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate (830 mg, 2.3 mmol) in THF(85 mL) at 0° C. was added NaH (415 mg, 17.3 mmol) in portions. Themixture was stirred at 0° C. for 1 h, then CS₂ (1.6 g, 21 mmol) wasadded dropwise and stirred for another 1 h. CH₃I (2.7 g, 19 mmol) wasadded dropwise at 0° C. and stirred for 1 h. The reaction wasconcentrated and then diluted with ethyl acetate (80 mL), washed withaqueous NH₄Cl (100 mL), aqueous layer was extracted with ethyl acetate(80 mL×3). The combined organic layers were washed by brine (50 mL),dried over Na₂SO₄, concentrated at low temperature to give methyl1-((6-cyclopropyl-8-(3-(methylthiocarbonothioyloxy)oxetan-3-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate(1 g, crude) as a yellow oil, which was used into next step withoutfurther purification. ESI-MS [M+H]⁺: 459.1

Synthesis of Methyl1-((6-cyclopropyl-8-(oxetan-3-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate

A mixture of methyl 1-((6-cyclopropyl-8-(3-(methylthiocarbonothioyloxy)oxetan-3-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate(1 g from previous step), Bu₃SnH (3.28 g, 11 mmol), AIBN (609 mg, 3.7mmol) in toluene (80 mL) was stirred at 120° C. for 0.5 h. The reactionwas concentrated and purified by silica gel column chromatography(DCM/MeOH=10/1) to give methyl1-((6-cyclopropyl-8-(oxetan-3-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate(490 mg, 61% yield over 2 steps) as a yellow oil. ESI-MS [M+H]⁺: 353.2.¹H NMR (400 MHz, DMSO-d₆) δ 8.38 (d, J=0.5 Hz, 1H), 8.24 (d, J=1.5 Hz,1H), 7.88 (d, J=0.6 Hz, 1H), 7.68 (s, 1H), 7.06-7.00 (m, 1H), 5.45 (s,2H), 4.93 (dd, J=8.6, 5.8 Hz, 2H), 4.83 (dd, J=7.1, 5.8 Hz, 2H),4.72-4.60 (m, 1H), 3.73 (s, 3H), 1.95 (qd, J=8.5, 4.3 Hz, 1H), 0.92(ddd, J=8.3, 6.3, 4.2 Hz, 2H), 0.76-0.69 (m, 2H).

Synthesis of1-((6-cyclopropyl-8-(oxetan-3-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylicAcid

A mixture of methyl1-((6-cyclopropyl-8-(oxetan-3-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate(50 mg, 0.14 mmol) and LiOH (24 mg, 0.57 mmol) in MeOH/THF/H₂O (1 mL/1mL/1 mL) was stirred at RT for 16 h. The reaction was adjusted to pH-3with HCl (1N), and concentrated to give1-((6-cyclopropyl-8-(oxetan-3-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylicacid (80 mg, crude) as a yellow solid, which was used into next stepwithout further purification. ESI-MS [M+H]⁺: 339.2. ¹H NMR (400 MHz,DMSO-d₆) δ 11.72 (s, 1H), 8.29 (s, 1H), 8.25 (s, 1H), 7.81 (s, 1H), 7.69(s, 1H), 7.03 (s, 1H), 5.44 (s, 2H), 4.93 (dd, J=8.6, 5.8 Hz, 2H), 4.83(dd, J=7.1, 5.9 Hz, 2H), 4.65 (dd, J=16.1, 8.1 Hz, 1H), 1.97 (dd, J=7.0,3.7 Hz, 1H), 0.95-0.89 (m, 2H), 0.72 (dt, J=6.4, 4.4 Hz, 2H).

Synthesis ofN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(oxetan-3-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(I-215)

A mixture of1-((6-cyclopropyl-8-(oxetan-3-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylicacid (80 mg, crude from last step),(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride(33 mg, 0.14 mmol), HATU (114 mg, 0.3 mmol) and DIPEA (38.7 mg, 0.3mmol) in DMF (3 mL) was stirred at RT for 16 h. The reaction mixture waspoured into H₂O (20 mL) and extracted with ethyl acetate (20 mL×3), thecombined organic layers were concentrated to give the crude, which waspurified by Prep-HPLC to giveN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(oxetan-3-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(15 mg, 20% yield) as a white solid. ESI-MS [M+H]⁺: 520.1. Purity:100.00% (214 nm), 100.00% (254 nm). ¹H NMR (400 MHz, DMSO-d₆) δ8.48-8.37 (m, 2H), 8.27-8.14 (m, 3H), 7.86 (s, 1H), 7.67 (s, 1H), 7.03(s, 1H), 6.76 (dd, J=7.3, 6.5 Hz, 1H), 5.39 (s, 2H), 4.93 (dd, J=8.5,5.8 Hz, 2H), 4.82 (dd, J=7.1, 5.9 Hz, 2H), 4.70-4.58 (m, 3H), 1.98-1.91(m, 1H), 0.95-0.89 (m, 2H), 0.76-0.67 (m, 2H).

Example 216

Synthesis of Ethyl1-((6-cyclopropyl-8-(2-oxooxazolidin-3-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate

A mixture of ethyl1-((8-bromo-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(196 mg, 0.5 mmol), CuI (48.5 mg, 0.25 mmol), dimethylglycine (25.7 mg,0.25 mmol), K₂CO₃ (140.4 mg, 1 mmol) and oxazolidin-2-one (50.4 mg, 0.55mmol) in dioxane (6 mL) was degassed by N2 for 10 min in a sealed tube.The reaction mixture was heated to 120° C. for 15 h. The reactionmixture was cooled to RT and then partitioned between saturated aqueousNH₄Cl (40 mL) and EtOAc (50 mL×3). The combined organic layers werewashed with brine, dried over Na₂SO₄, concentrated under vacuum to givethe crude, which was purified by silica gel chromatography (DCM/EA:3/1-1/1) to afford ethyl1-((6-cyclopropyl-8-(2-oxooxazolidin-3-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylateas a white solid (70 mg, yield: 35.4%). ESI-MS [M+H]⁺: 396.7.

Synthesis of lithium1-((6-cyclopropyl-8-(2-oxooxazolidin-3-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate

To a solution of ethyl1-((6-cyclopropyl-8-(2-oxooxazolidin-3-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(70 mg, 0.18 mmol) in THF (3 mL) and H₂O (3 mL) was added LiOH.H₂O (24mg, 0.54 mmol) and the reaction mixture was stirred at RT for 15 h. ThepH of the reaction was adjusted by HCl (1N) to 4, and then lyophilizedto afforded crude1-((6-cyclopropyl-8-(2-oxooxazolidin-3-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid as white solid which was used directly for the next step withoutfurther purification (100 mg crude). ESI-MS [M+H]⁺: 368.7.

Synthesis ofN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(2-oxooxazolidin-3-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(I-216)

To the crude of1-((6-cyclopropyl-8-(2-oxooxazolidin-3-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (100 mg, crude from previous step) in DMF (4 mL) was added(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride(43 mg, 0.18 mmol), DIPEA (47.1 mg, 0.36 mmol) and HATU (101.4 mg, 0.27mmol) in sequence. The mixture was stirred at RT for 3.5 h. The reactionwas diluted with H₂O (30 mL), extracted with EtOAc (30 mL×3). Thecombined organic layers were washed with brine, dried over Na₂SO₄,concentrated to give the crude, which was purified by prep-HPLC toaffordN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(2-oxooxazolidin-3-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamideas a white solid (24.1 mg, 24% over 2 steps). ESI-MS [M+H]⁺: 549.5.Purity: 98.29 (214 nm) 97.72 (254 nm). ¹H NMR (400 MHz, DMSO-d₆) δ 8.72(s, 1H), 8.56 (s, 1H), 8.45 (s, 1H), 8.34 (s, 1H), 8.20 (d, J=7.4 Hz,1H), 7.93 (s, 1H), 7.35 (s, 1H), 6.76 (t, J=6.8 Hz, 1H), 5.78 (s, 2H),4.70 (d, J=5.4 Hz, 2H), 4.49 (t, J=7.7 Hz, 2H), 4.35 (t, J=7.8 Hz, 2H),1.96 (s, 1H), 0.98-0.92 (m, 2H), 0.70-0.65 (m, 2H).

Example 217

Synthesis of 6-chloropyridazin-4-amine

A solution of 3,5-dichloropyridazine (9 g, 60.8 mmol) in NH₄OH (25%, 100mL) was stirred at 120° C. for 16 h in sealed tube. Then the mixture wasconcentrated in vacuo and triturated with ether to give the6-chloropyridazin-4-amine as a brown solid (7.3 g, yield: 93%). ESI-MS[M+H]⁺: 130.0.

Synthesis of 5-bromo-3-chloropyridazine

To a solution 6-chloropyridazin-4-amine (2 g, 15 mmol), t-BuONO (2.4 g,23 mmol) in MeCN (40 mL) was added CuBr₂ (5 g, 23 mmol) at 0° C. Theresulting mixture was stirred at RT for 16 h and then concentrated invacuo. The mixture was diluted with EtOAc (50 mL) and added H₂O (50 mL).After filtered through celite, the filtrate was extracted with EtOAc (50mL×3). The combined organic layers were washed with brine, dried overNa₂SO₄, and concentrated to give the crude product which was purified bysilica gel chromatography (PE/EA=20/1) to give5-bromo-3-chloropyridazine (1.32 g, yield: 43%) as a brown oil. ESI-MS[M+H]⁺: 192.8, 194.8.

Synthesis of 3-chloro-5-cyclopropylpyridazine

To a mixture of 5-bromo-3-chloropyridazine (1.3 g, 6.7 mmol), Pd(OAc)₂(156 mg, 0.67 mmol), P(Cy)₃ (196 mg, 0.67 mmol), K₃PO₄ (2.9 g, 13.4mmol) in dioxane/H₂O (30 mL/8 mL) was added cyclopropylboronic acid (1.1g, 13.4 mmol) at RT and stirred at 100° C. for 16 h. The mixture wasconcentrated and purified by silica gel chromatography (PE/EA=5/1) togive 3-chloro-5-cyclopropylpyridazine (280 mg, yield: 27%) as a brownoil. ESI-MS [M+H]⁺: 155.1

Synthesis of 5-cyclopropylpyridazin-3-amine

A mixture of 3-chloro-5-cyclopropylpyridazine (500 mg, 3.2 mmol),CH₃ONH₂—HCl (531 mg, 6.4 mmol) in EtOH (20 mL) was stirred 90° C. for 16h. After concentrated under reduced pressure, to the mixture was addedFe powder (900 mg, 16 mmol), 20% AcOH (10 mL) in EtOH (20 mL). Themixture was stirred 60° C. for 6 h and then neutralized by aqueousNaHCO₃. After filtered through celite, the mixture was extracted withEtOAc (60 mL*3). The combined organic layers were washed with brine,dried over Na₂SO₄, and concentrated to give the crude product which waspurified by silica gel chromatography (PE/EA=3/1) to give5-cyclopropylpyridazin-3-amine (180 mg, yield: 41%) as a brown solid.ESI-MS [M+H]⁺: 136.0.

Synthesis of 2-(chloromethyl)-7-cyclopropylimidazo[1,2-b]pyridazine

To a solution of 5-cyclopropylpyridazin-3-amine (400 mg, 3 mmol) indioxane (10 mL) was added 1,3-dichloropropan-2-one (780 mg, 6 mmol) atRT. The reaction mixture was stirred at 100° C. for 16 h and thenneutralized by aqueous NaHCO₃. Water (20 mL) was added and the mixturewas extracted with DCM (50 mL×2). The combined organic layers wereconcentrated and purified by silica gel chromatography (PE/EA=4/1) togive 2-(chloromethyl)-7-cyclopropylimidazo[1,2-b]pyridazine (160 mg,yield: 26%) as a brown solid. ESI-MS [M+H]⁺: 207.9.

Synthesis of 2-(azidomethyl)-7-cyclopropylimidazo[1,2-b]pyridazine

A solution of ethyl2-(chloromethyl)-7-cyclopropylimidazo[1,2-b]pyridazine (160 mg, 0.77mmol) in DMF (5 mL) was added NaN₃ (97 mg, 1.5 mmol) at and stirred atRT for 10 h. The reaction was diluted with H₂O (30 mL) and extractedwith DCM (50 mL×3). The combined organic layers were concentrated andpurified by silica gel chromatography (PE/EA=4/1) to give2-(azidomethyl)-7-cyclopropylimidazo[1,2-b]pyridazineine (140 mg, yield:85%) as a white solid. ESI-MS [M+H]⁺: 215.1.

Synthesis of Methyl1-((7-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate

A mixture of 2-(azidomethyl)-7-cyclopropylimidazo[1,2-b]pyridazineine(140 mg, 0.65 mmol), methyl propiolate (84 mg, 1 mmol), CuSO₄.5H₂O (35mg, 0.14 mmol), sodium ascorbate (40 mg, 0.2 mmol) in t-BuOH/H₂O (4 mL/4mL) was stirred at RT for 16 h. The mixture was concentrated in vacuo togive the crude product which was purified by silica gel chromatography(PE/EA=1/4) to give methyl1-((7-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(180 mg, yield: 88%) as a white solid. ESI-MS [M+H]⁺: 312.9.

Synthesis of1-((7-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicAcid

A mixture of1-((7-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(180 mg, 0.58 mmol), NaOH (48 mg, 1.2 mmol) in THF/EtOH/H₂O (4 mL/4 mL/4mL) was stirred at RT for 0.5 h. The mixture was acidified with 1N HClsolution, concentrated in vacuo to give the crude product of methyl1-((7-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (250 mg, crude) as a white solid. ESI-MS [M+H]⁺: 285.0.

Synthesis ofN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((7-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(I-217)

A mixture of1-((7-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (125 mg, crude),(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride(118 mg, 0.5 mmol), EDCI (105 mg, 0.55 mmol), HOBT (74 mg, 0.55 mmol),DIPEA (161 mg, 1.25 mmol) in DMF (5 mL) was stirred at RT for 16 h. Thereaction was poured into H₂O (30 mL), solid was filtered and washed byH₂O (10 mL), EtOAc (10 mL), ether (10 mL) to give2-(azidomethyl)-7-cyclopropylimidazo [1,2-b]pyridazineine (20 mg) as awhite solid. ESI-MS [M+H]⁺: 466.8. Purity: 96.85 (214 nm), 97.30 (254nm). ¹H NMR (400 MHz, CDCl₃) δ 8.24 (s, 1H), 8.16 (s, 1H), 8.08 (s, 1H),7.86 (s, 1H), 7.66-7.64 (m, 2H), 7.45 (s, 1H), 6.51 (t, J=6.6 Hz, 1H),5.72 (s, 2H), 4.95 (d, J=5.1 Hz, 2H), 2.00-1.91 (m, 1H), 1.17-1.12 (m,2H), 0.85-0.81 (m, 2H).

Example 218

Synthesis of Ethyl 5-bromobenzo[b]thiophene-2-carboxylate

To a solution of 5-bromo-2-fluorobenzaldehyde (2.03 g, 10 mmol) andethyl 2-mercaptoacetate (1.2 g, 10 mmol) in EtOH (40 mL) was addedNa₂CO₃ (1.27 g, 12 mmol). The reaction mixture was stirred at reflux for14 h. Then the mixture was concentrated in vacuo. Water (20 mL) wasadded and the mixture was extracted with DCM (50 mL×3). The combinedorganic layers were concentrated to give the crude product, which waspurified by silica gel chromatography (PE/EtOAc=1/1) to give the ethyl5-bromobenzo[b]thiophene-2-carboxylate as a yellow solid (2.3 g, yield:80%). ESI-MS [M+H]⁺: 284.7, 286.7.

Synthesis of Ethyl 5-cyclopropylbenzo[b]thiophene-2-carboxylate

A solution of 5-bromobenzo[b]thiophene-2-carboxylate (2.3 g, 8 mmol),cyclopropylboronic acid (1.7 g, 20 mmol), Pd(OAc)₂ (180 mg, 0.8 mmol),PCy₃ (448 mg, 1.6 mmol) and K₃PO₄ (4.24 g, 20 mmol) in toluene (40mL)/MeOH (4 mL)/H₂O (4 mL) was stirred under reflux in nitrogenatmosphere overnight. The reaction mixture was concentrated to give aresidue. The residue was diluted with H₂O (30 mL) and extracted withEtOAc (50 mL×3). The combined organic layers were washed with brine (20mL), dried over Na₂SO₄, filtered and concentrated to give the crudeproduct which was purified by flash column chromatography (PE/EA=10/1)to give the product ethyl 5-cyclopropylbenzo[b]thiophene-2-carboxylate(730 mg, 37%) as a light yellow solid. ESI-MS [M+H]⁺: 246.9.

Synthesis of (5-cyclopropylbenzo[b]thiophen-2-yl)methanol

To a stirring solution of 5-cyclopropylbenzo[b]thiophene-2-carboxylate(180 mg, 0.73 mmol) in dry THF (15 mL) was added portion-wise LiAlH₄ (84mg, 2.19 mmol) under ice H₂O bath. The resulting mixture was stirred at0° C. for 1 h. The reaction was quenched sequentially with H₂O (0.5 mL),15% NaOH (0.5 mL) and H₂O (1.5 mL). The resulting mixture was filteredand the filtrate was concentrated to give the crude product(5-cyclopropylbenzo[b]thiophen-2-yl)methanol (130 mg) as a light yellowoil which was used into next step directly. ESI-MS [M+H]⁺: 205.0

Synthesis of 2-(azidomethyl)-5-cyclopropylbenzo[b]thiophene

To a stirring solution of (5-cyclopropylbenzo[b]thiophen-2-yl)methanol(130 mg, 0.64 mmol) and DPPA (211 mg, 0.77 mmol) in dry THF (20 mL) wasadded DBU (116 mg, 0.77 mmol) under ice H₂O bath. The resulting mixturewas stirred at RT overnight. The reaction mixture was concentrated togive a residue which was purified by flash column chromatography(DCM/MeOH=20/1) to give the product2-(azidomethyl)-5-cyclopropylbenzo[b]thiophene (120 mg, 82%) as a lightyellow oil. ESI-MS [M+H]⁺: 230.0.

Synthesis of Ethyl1-((5-cyclopropylbenzo[b]thiophen-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate

A solution of 2-(azidomethyl)-5-cyclopropylbenzo[b]thiophene (120 mg,0.52 mmol) in t-BuOH (3 mL) and H₂O (3 mL) was added sequentially ofCuSO₄-5H₂O (26 mg, 0.104 mmol), sodium ascorbate (25 mg, 0.123 mmol) andethyl propiolate (101 mg, 1.04 mmol). The resulting mixture was stirredat RT for 15 h. The reaction mixture was concentrated to give the crudeproduct. The crude product was purified by flash column chromatography(DCM/MeOH=20/1) to give the product ethyl1-((5-cyclopropylbenzo[b]thiophen-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(80 mg, 47%) as a light yellow oil. ESI-MS [M+H]⁺: 327.8

Synthesis of1-((5-cyclopropylbenzo[b]thiophen-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicAcid

A solution of ethyl1-((5-cyclopropylbenzo[b]thiophen-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(80 mg, 0.24 mmol) and LiOH.H₂O (29 mg, 0.72 mmol) in MeOH/H₂O (5 mL/5mL) was stirred at RT for 2 h. The volatile was removed in vacuo and theaqueous phase was acidified to pH 4-5 with 2N HCl. Concentrated in vacuoto give the crude product1-((5-cyclopropylbenzo[b]thiophen-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (100 mg, crude) as a yellow solid, which used directly in the nextstep without further purification. ESI-MS [M+H]⁺: 299.8.

Synthesis ofN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((5-cyclopropylbenzo[b]thiophen-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(I-218)

To a solution of1-((5-cyclopropylbenzo[b]thiophen-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (100 mg, crude),(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine (100 mg, 0.17),EDCI (38 mg, 0.2 mmol) and HOBT (27 mg, 0.2 mmol) in DMF (5 mL) wasadded DIPEA (64 mg, 0.5 mmol). The resulting mixture was stirred at RTfor 15 h. The reaction mixture was diluted with H₂O (30 mL). Then it wasextracted with EtOAc (30 mL*3). The combined organic layer was washedwith brine, dried over Na₂SO₄ and concentrated. The residue was purifiedby flash column chromatography (DCM/MeOH=10/1) to give the productN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((5-cyclopropylbenzo[b]thiophen-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(17 mg, yield: 20%) as a white solid. ESI-MS [M+H]⁺: 481.1 Purity: 96.52(214 nm), 96.66 (254 nm). ¹H NMR (400 MHz, DMSO-d₆) δ 8.76 (s, 1H), 8.67(s, 1H), 8.45 (s, 1H), 8.21 (d, J=7.1 Hz, 1H), 7.78 (d, J=8.1 Hz, 1H),7.55 (s, 1H), 7.39 (s, 1H), 7.09 (d, J=7.7 Hz, 1H), 6.76 (s, 1H), 5.97(s, 2H), 4.71 (s, 2H), 2.06-1.96 (m, 1H), 1.03-0.92 (m, 2H), 0.75-0.66(m, 2H).

Example 219

Synthesis of Ethyl 6-bromobenzofuran-2-carboxylate

A solution of 4-bromo-2-hydroxybenzaldehyde (2.01 g, 10 mmol) and ethyl2-bromoacetate (1.9 g, 12 mmol) in DMF (20 mL). The reaction mixture wasstirred at 75° C. overnight. Then the mixture was concentrated in vacuo.Water (50 mL) was added and the mixture was extracted with DCM (50mL×3). The combined organic layer was washed with brine, dried overNa₂SO₄ and concentrated to give the crude product which was purified bysilica gel chromatography (PE/EtOAc=1/1) to give ethyl6-bromobenzofuran-2-carboxylate as a yellow solid (1.6 g, yield: 59%).ESI-MS [M+H]⁺: 268.7, 270.7.

Synthesis of Ethyl Ethyl 6-cyclopropylbenzofuran-2-carboxylate

A mixture of ethyl 6-bromobenzofuran-2-carboxylate (800 mg, 3 mmol),cyclopropylboronic acid (638 g, 7.5 mmol), Pd(OAc)₂ (67.5 mg, 0.3 mmol),PCy₃ (138 mg, 0.6 mmol) and K₃PO₄ (1.59 g, 7.5 mmol) in dioxane (20 mL)and H₂O (2 mL) was stirred under reflux in nitrogen atmosphereovernight. The reaction mixture was diluted with H₂O (50 mL), thenextracted with EtOAc (50 mL×3). The combined organic layers were washedwith brine, dried over Na₂SO₄ and concentrated. The crude product waspurified by flash column chromatography (PE/EA=10/1) to give ethyl ethyl6-cyclopropylbenzofuran-2-carboxylate (360 mg, 52%) as a light yellowsolid. ESI-MS [M+H]⁺: 230.9.

Synthesis of (5-cyclopropylbenzo[b]thiophen-2-yl)methanol

To a stirring solution of ethyl 6-cyclopropylbenzofuran-2-carboxylate(360 mg, 1.56 mmol) in dry THF (15 mL) was added portion-wise LiAlH₄(177 mg, 4.68 mmol) under ice H₂O bath. The resulting mixture wasstirred at 0° C. for 1 h. The reaction was quenched sequentially withH₂O (0.2 mL), 15% NaOH (0.2 mL) and H₂O (0.6 mL). The resulting mixturewas filtered and the filtrate was concentrated to give(6-cyclopropylbenzofuran-2-yl)methanol (280 mg, crude) as a light yellowoil which was used for next step directly. ESI-MS [M+H]⁺: 171.0

Synthesis of 2-(azidomethyl)-6-cyclopropylbenzofuran

To a stirring solution of (6-cyclopropylbenzofuran-2-yl)methanol (280mg, crude) and DPPA (493 mg, 1.8 mmol) in dry THF (20 mL) was added DBU(271 mg, 1.8 mmol) under ice H₂O bath. The resulting mixture was stirredat RT overnight. The reaction mixture was diluted with H₂O (30 mL) andextracted with EtOAc (30 mL×3). The combined organic layers were washedwith brine, dried over Na₂SO₄ and concentrated. The residue was purifiedby flash column chromatography (DCM/MeOH=20/1) to give2-(azidomethyl)-6-cyclopropylbenzofuran (228 mg, 68% over 2 steps) as apale-yellow oil. ESI-MS [M+H]⁺: 214.0.

Synthesis of Ethyl1-((6-cyclopropylbenzofuran-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate

A solution of 2-(azidomethyl)-6-cyclopropylbenzofuran (228 mg, 1.07mmol) in t-BuOH (3 mL) and H₂O (3 mL) was added sequentially ofCuSO₄-5H₂O (53 mg, 0.214 mmol), sodium ascorbate (55 mg, 0.270 mmol) andethyl propiolate (2.07 mg, 2.14 mmol). The resulting mixture was stirredat RT for 15 h. The reaction mixture was diluted with H₂O (50 mL). Thenit was extracted with EtOAc (50 mL×3). The combined organic layers werewashed with brine, dried over Na₂SO₄ and concentrated. The crude productwhich was purified by flash column chromatography (DCM/MeOH=20/1) togive ethyl1-((6-cyclopropylbenzofuran-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(140 mg, 42%) as a light yellow oil. ESI-MS [M+H]⁺: 311.8

Synthesis of1-((6-cyclopropylbenzofuran-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicAcid

A solution of ethyl1-((6-cyclopropylbenzofuran-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(140 mg, 0.45 mmol) and LiOH.H₂O (54 mg, 1.35 mmol) in MeOH/H₂O (10mL/10 mL) was stirred at RT for 2 h. The volatiles were removed in vacuoand the aqueous phase was acidified to pH 4-5 with 2N HCl, thenconcentrated in vacuo to give1-((6-cyclopropylbenzofuran-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (200 mg, crude) as a yellow solid, which was used directly in thenext step without further purification. ESI-MS [M+H]⁺: 300.1

Synthesis ofN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylbenzofuran-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(I-218)

To a solution of1-((6-cyclopropylbenzofuran-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (200 mg, crude),(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride(100 mg, 0.42), EDCI (93 mg, 0.5 mmol) and HOBT (68 mg, 0.5 mmol) in DMF(5 mL) was added DIPEA (80 mg, 1.25 mmol). The resulting mixture wasstirred at RT for 15 h. The reaction mixture was diluted with H₂O (30mL), then extracted with EtOAc (50 mL×3). The combined organic layerswere washed with brine, dried over Na₂SO₄ and concentrated. The residuewas purified by flash column chromatography (DCM/MeOH=10/1) to giveN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylbenzofuran-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(17 mg, 8.7%) as a white solid. ESI-MS [M+H]⁺: 464.7. Purity: 98.95 (214nm), 98.84 (254 nm). ¹H NMR (400 MHz, DMSO-d₆) δ 8.75 (s, 1H), 8.62 (s,1H), 8.44 (s, 1H), 8.21 (d, J=7.4 Hz, 1H), 7.49 (d, J=8.1 Hz, 1H), 7.23(s, 1H), 7.02 (d, J=8.1 Hz, 1H), 6.96 (s, 1H), 6.76 (t, J=6.7 Hz, 1H),5.87 (s, 2H), 4.70 (d, J=5.1 Hz, 2H), 2.04-1.94 (m, 1H), 0.99-0.91 (m,2H), 0.73-0.66 (m, 2H).

Example 220

Synthesis of1-((6-cyclopropyl-8-(1H-pyrazol-1-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicAcid

A mixture of ethyl1-((8-bromo-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(300 mg, 0.77 mmol), 1H-pyrazole (130 mg, 1.93 mmol), CuI (15 mg, 0.077mmol), (1R,2R)—N1,N2-dimethylcyclohexane-1,2-diamine (22 mg, 0.154 mmol)and Cs₂CO₃ (550 mg, 1.70 mmol) in DMA (5 mL) was degassed by N2 for 10min in a sealed tube. The reaction mixture was stirred at 150° C. for 12h. Then the mixture was poured into 30 mL of H₂O, extracted with EtOAc(30 mL×3). The combined organic layers were washed with brine, driedover Na₂SO₄, concentrated in vacuo to give1-((6-cyclopropyl-8-(H-pyrazol-1-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (300 mg, crude) which was used in next step without furtherpurification. ESI-MS [M+H]⁺: 349.8.

Synthesis ofN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(1H-pyrazol-1-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(I-220)

To a solution of1-((6-cyclopropyl-8-(H-pyrazol-1-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (300 mg, crude from previous step) in DMF (5 mL) was added EDCI(145 mg, 0.756 mmol), HOBT (103 mg, 0.756 mmol), DIPEA (0.32 mL, 1.72mmol) and (7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanaminehydrochloride (179 mg, 0.756 mmol). The reaction mixture was stirred atRT for 12 h. The mixture was poured into 20 mL of H₂O, extracted withEtOAc (30 mL×3). The combined organic layers were washed with brine,dried over Na₂SO₄, and concentrated to give the crude product which waspurified by prep-HPLC to giveN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(1H-pyrazol-1-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(36 mg, 9% over 2 steps) as a white solid. ESI-MS [M+H]⁺: 530.8. Purity:97.94 (214 nm) 97.53 (254 nm). ¹H NMR (400 MHz, DMSO-d₆) S=9.28 (s, 1H),8.73 (t, J=4.0 Hz, 1H), 8.63 (s, 1H), 8.47 (s, 1H), 8.40 (s, 1H), 8.21(d, J=4.0 Hz, 1H), 8.02 (s, 1H), 7.85 (s, 1H), 7.66 (s, 1H), 6.77 (t,J=4.0 Hz, 1H), 6.60 (s, 1H), 5.84 (s, 2H), 4.70 (d, J=4.0 Hz, 2H),1.24-1.21 (m, 1H), 0.98 (dd, J=8.0, 4.0 Hz, 2H), 0.74 (dd, J=8.0, 4.0Hz, 2H).

Example 221

Synthesis of1-((6-cyclopropyl-8-((1-methoxycarbonyl)cyclopentyl)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicAcid

To a mixture of methyl cyclopentanecarboxylate (330 mg, 2.58 mmol) inTHF (10 mL) was added LDA (2.0 M, 1.48 mL, 2.967 mmol) dropwise at −78°C. and the mixture was stirred at −78° C. for 4 h. tert-butyl1-((8-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(500 mg, 1.29 mmol) in THF (5 mL) was added to the reaction mixturedropwise. The resulting reaction mixture was warmed to RT and stirred atRT for 2 h. NH₄Cl aq. added to the reaction mixture and extracted withEtOAc (30 mL×3). The organic layers were washed by brine, dried overNa₂SO₄ and concentrated to afford1-((6-cyclopropyl-8-((1-(methoxycarbonyl)cyclopentyl)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (157 mg, yield: 29%) which was used in next step directly. ESI-MS[M+H]⁺: 424.1

Synthesis of Methyl1-((2-((4-(((7-chloro-S-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)methyl)cyclopentane-1-carboxylate (I-221a)

A solution of1-((6-cyclopropyl-8-((1-(methoxycarbonyl)cyclopentyl)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (157 mg, 0.37 mmol),(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride(113 mg, 0.48 mmol), HOBT (100 mg, 0.74 mmol), EDCI (142 mg, 0.74 mmol)and DIPEA (239 mg, 1.85 mmol) in DMF (5 mL) was stirred at RT for 16 h.The reaction mixture was diluted with H₂O (50 mL). Then it was extractedwith EtOAc (50 mL×3). The combined organic layers were washed withbrine, dried over Na₂SO₄ and concentrated. The residue was purified byPrep-TLC (DCM:MeOH=10:1) to give methyl1-((2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)methyl)cyclopentane-1-carboxylate(102 mg, 46%). ESI-MS [M+H]⁺: 605.2. Purity: 98.88 (214 nm), 98.20 (254nm). ¹H NMR (400 MHz, DMSO-d₆) δ 8.67 (t, J=6.0 Hz, 1H), 8.50 (s, 1H),8.44 (d, J=4 Hz, 1H), 8.22-8.19 (m, 2H), 7.79 (s, 1H), 6.78-6.74 (m,1H), 6.61 (d, J=4.0 Hz, 1H), 5.71 (s, 2H), 4.70 (d, J=4.0 Hz, 1H), 3.50(s, 3H), 3.17-3.16 (m, 4H), 1.91-1.86 (m, 3H), 1.63-1.62 (s, 4H),0.93-0.89 (m, 2H), 0.62-0.58 (m, 2H).

Synthesis of1-((2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)methyl)cyclopentane-1-carboxylicacid (I-221b) and1-((2-((4-(((7-chloro-8-ethoxyimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)methyl)cyclopentane-1-carboxylicacid (I-221c)

A solution of methyl1-((2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)methyl)cyclopentane-1-carboxylate(91 mg, 0.15 mmol) and NaOH (20 mg, 0.45 mmol) in EtOH (3 mL) and H₂O (1mL) was stirred at RT for 16 h. The solvent was removed under reducedpressure and the residue was purified by reversed phase flashchromatography (acetonitrile:H₂O=5% to 95%) to give1-((2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)methyl)cyclopentane-1-carboxylicacid (50 mg, yield: 57%) and1-((2-((4-(((7-chloro-8-ethoxyimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)methyl)cyclopentane-1-carboxylicacid. (7 mg, 8%). I-221b: ESI-MS [M+H]⁺: 591.1. Purity: 96.55 (214 nm),98.91 (254 nm). ¹H NMR (400 MHz, DMSO-d₆) δ 8.68 (t, J=8.0 Hz, 1H), 8.51(s, 1H), 8.44 (d, J=4 Hz, 1H), 8.21-8.19 (m, 2H), 7.78 (s, 1H), 6.76 (t,J=4.0 Hz, 1H), 6.71 (s, 1H) 5.72 (s, 2H), 4.70 (d, J=4.0 Hz, 2H), 3.17(s, 2H), 1.91-1.83 (m, 3H), 1.55 (s, 5H), 0.91-0.88 (m, 2H), 0.60-0.58(m, 2H). I-221c: ESI-MS [M+H]⁺: 617.2. Purity: 99.56 (214 nm), 100.0(254 nm). ¹H NMR (400 MHz, DMSO-d₆) δ 12.35 (s, 1H), 8.53 (s, 1H), 8.42(t, J=6.0 Hz, 1H), 8.37 (s, 1H), 8.21 (s, 1H), 8.13 (d, J=8.0 Hz, 1H),7.78 (s, 1H), 6.71 (s, 1H), 6.67 (t, J=8.0 Hz, 1H), 5.73 (s, 2H), 4.76(d, J=8.0 Hz, 2H), 4.23 (q, J=6.7 Hz, 2H), 3.18 (s, 2H), 1.92-1.83 (m,3H), 1.60-1.50 (m, 6H), 1.40 (t, J=6.0 Hz, 3H), 0.93-0.88 (m, 2H),0.62-0.58 (m, 2H).

Example 222

Synthesis of Ethyl6-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-2-carboxylate

To a solution of ethyl 6-chloro-1H-indole-2-carboxylate (2 g, 8.9 mmol)in THF (15 mL) was added NaH (890 mg, 60 wt %, 13.35 mmol) portion-wiseat 0° C. The mixture was stirred at RT for 1 h. SEMCl (1.6 g, 9.8 mmol)was added at 0° C. The reaction mixture was stirred at RT for 2 h.Quenched with H₂O (50 mL) and extracted with EtOAc (50 mL×3), thecombined organic layers were washed by brine, dried over Na₂SO₄, andconcentrated to give ethyl6-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-2-carboxylate (3g, yield: 95%) as a yellow solid which was used in next step directly.ESI-MS [M+H]⁺: 354.0.

Synthesis of(6-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-2-yl)methanol

To a solution of LiAlH₄ (405 mg, 10 mmol) in THF (15 mL) was added ethyl6-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-2-carboxylate (3g, 8.5 mmol) in THF (15 mL) dropwise at 0° C. The reaction mixture wasstirred at RT for 2 h, then quenched with H₂O (2 mL) at 0° C. andfiltered. The filtrate was concentrated to give(6-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-2-yl)methanol (2g) as a brown oil, which was used into next step directly. ESI-MS[M+1]⁺: 312.1

Synthesis of6-chloro-2-(chloromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole

A mixture of(6-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-2-yl)methanol(1.5 g, crude from last step), MsCl (826 mg, 7.2 mmol) and TEA (1.4 g,14.4 mmol) in DCM (10 mL) was stirred at RT for 3 h. Water (50 mL) wasadded and extracted with DCM (50 mL×3), combined organic layers wereconcentrated to give6-chloro-2-(chloromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole(1.5 g, crude) as a yellow solid.

Synthesis of2-(azidomethyl)-6-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole

A mixture of6-chloro-2-(chloromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole(1.5 g, crude from last step) and NaN₃ (374 mg, 5.76 mmol) in DMF (5 mL)was stirred at RT overnight. Water (50 mL) was added and extracted withEtOAc (50 mL×3). The combined organic layers were washed by brine (20mL×2), dried over Na₂SO₄, concentrated. The residue was purified bysilica gel (PE/EA=10/1) to give2-(azidomethyl)-6-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole(200 mg) as a yellow oil.

Synthesis of Ethyl1-((6-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate

A mixture of2-(azidomethyl)-6-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole(200 mg, 0.59 mmol), ethyl propiolate (175 mg, 1.78 mmol), CuSO₄ (47 mg,0.3 mmol) and sodium ascorbate (53 mg, 0.3 mmol) in H₂O/t-BuOH (5 mL/5mL) was stirred at RT for 3 h. The reaction mixture was diluted with H₂O(30 mL). Then it was extracted with EtOAc (50 mL×3). The combinedorganic layers were washed with brine, dried over Na₂SO₄ andconcentrated. The residue was purified by silica gel (CH₂Cl₂/MeOH=10/1)to give ethyl1-((6-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(200 mg, yield: 78%) as a yellow solid. ESI-MS [M+Na]+: 457.1.

Synthesis of Ethyl1-((6-chloro-1H-indol-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate

To a solution of ethyl1-((6-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(120 mg, 0.27 mmol) in DCM (10 mL) was added TFA (1 mL) at 0° C. Thereaction mixture was stirred at RT for 6 h. NH₃.H₂O was added until pHto 9 at 0° C. Concentrated, the residue was purified by silica gel(CH₂Cl₂/MeOH=10/1) to give ethyl1-((6-chloro-1H-indol-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate (27mg, yield: 33%) as a yellow oil. ESI-MS [M+Na]+: 327.0.

Synthesis of1-((6-chloro-1H-indol-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic Acid

A mixture of ethyl1-((6-chloro-1H-indol-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate (27mg, 0.09 mmol) and LiOH.H₂O (8 mg, 0.18 mmol) in THF/EtOH/H₂O (1 mL/1mL/0.5 mL) was stirred at 50° C. for 1 h. Water (5 mL) was added, pH ofthe mixture was adjusted to 5 by HCl (2 M). Extracted with EtOAc (30mL×5). The combined organic layers were was washed with brine, driedover Na₂SO₄ and concentrated to give1-((6-chloro-1H-indol-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid(25 mg, crude) as a white solid which was used into next step directly.ESI-MS [M+Na]+: 299.1

Synthesis of1-((6-chloro-1H-indol-2-yl)methyl)-N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(I-222)

A mixture of1-((6-chloro-1H-indol-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid(25 mg, crude from last step),(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride(24 mg, 0.1 mmol), HOBT (27 mg, 0.2 mmol), EDCI (38 mg, 0.2 mmol) andDIPEA (65 mg, 0.5 mmol) in DMF (2.5 mL) was stirred at RT for 16 h.Water (20 mL) was added and extracted with EtOAc (30 mL×3). The combinedorganic layers were washed by brine, dried over Na₂SO₄ and concentrated.The residue was purified by prep-HPLC to give1-((6-chloro-1H-indol-2-yl)methyl)-N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(16.1 mg, yield: 38% over 2 steps) as a white solid. ESI-MS [M+H]⁺:458.0. Purity: 98.76 (214 nm), 99.73 (254 nm). ¹H NMR (400 MHz, DMSO-d₆)δ 11.47 (s, 1H), 8.72 (t, J=5.4 Hz, 1H), 8.58 (s, 1H), 8.43 (d, J=2.4Hz, 1H), 8.20 (d, J=7.4 Hz, 1H), 7.51 (d, J=8.4 Hz, 1H), 7.39 (s, 1H),7.00 (dd, J=8.4 Hz, J=1.9 Hz, 1H), 6.77-6.74 (m, 1H), 6.49 (d, J=1.0 Hz,1H), 5.79 (s, 2H), 4.69 (d, J=5.5 Hz, 2H).

Example 223

Synthesis of Ethyl2-((2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)oxy)-2-methylpropanoate(I-223)

To a mixture of2-((2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)oxy)-2-methylpropanoicacid (90 mg, 0.16 mmol) in EtOH (5 mL) was added SOCl₂ (0.5 mL). Themixture was stirred at RT for 12 h. After concentrated to give crude,which was purified with Prep-TLC (DCM/MeOH=10/1) to give ethyl2-((2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)oxy)-2-methylpropanoate(70 mg, yield: 74%) as a yellow solid. ESI-MS [M+H]⁺: 595.1. Purity:98.9 (214 nm), 100.0 (254 nm). ¹H NMR (400 MHz, DMSO-d₆) δ 8.79 (t,J=5.4 Hz, 1H), 8.68 (s, 1H), 8.52 (d, J=2.3 Hz, 1H), 8.33 (s, 1H), 8.23(d, J=7.4 Hz, 1H), 8.19 (s, 1H), 6.84-6.77 (m, 1H), 6.72 (s, 1H), 5.94(s, 2H), 4.71 (d, J=5.5 Hz, 2H), 4.18 (q, J=7.1 Hz, 2H), 2.10-2.03 (m,1H), 1.69 (s, 6H), 1.14 (t, J=7.1 Hz, 3H), 1.05-0.97 (m, 2H), 0.72-0.62(m, 2H).

Example 224

Synthesis of dimethyl2-((2-((4-(tert-butoxycarbonyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)methyl)-2-fluoromalonate

To a solution of compound dimethyl 2-fluoromalonate (0.54 g, 3.6 mmol)in anhydrous DMF (10 mL) was added NaH (140 mg, 3.6 mmol, 60% in mineraloil) and the reaction was stirred at 0° C. for 0.5 h under N₂atmosphere. Then the solution of tert-butyl1-((8-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(1 g, 2.5 mmol) in DMF (2 mL) was added, The resulting mixture wasstirred at 80° C. for 16 h. The reaction was quenched with saturatedaqueous NH₄Cl solution (20 mL), and extracted with ethyl acetate (100mL×2). The combined organic phases were dried over Na₂SO₄, evaporated togive the crude, which was purified with silica gel chromatography(DCM/MeOH=100/1) to give the dimethyl2-((2-((4-(tert-butoxycarbonyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)methyl)-2-fluoromalonate(1.1 g, 85%) as a yellow solids. ESI-MS [M+H]⁺: 502.3.

Synthesis of tert-butyl1-((6-cyclopropyl-8-(2-fluoro-3-methoxy-3-oxopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate

To a solution of compound dimethyl2-((2-((4-(tert-butoxycarbonyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)methyl)-2-fluoromalonate(500 mg, 1 mmol) in DMA (5 mL) was added lithium chloride (126 mg, 2.99mmol) and then the reaction mixture was stirred at 80° C. for 3 h. Aftercooling to RT, the reaction was quenched with H₂O (50 mL), extractedwith EtOAc (100 mL×3), washed with brine (50 mL), dried over sodiumsulfate, concentrated to give the residue, which was purified by silicagel chromatography (DCM/MeOH=50/1) to give the tert-butyl1-((6-cyclopropyl-8-(2-fluoro-3-methoxy-3-oxopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(440 mg, 99%) as yellow oil. ESI-MS [M+H]⁺: 444.2.

Synthesis of1-((6-cyclopropyl-8-(2-fluoro-3-methoxy-3-oxopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicAcid

To a solution of tert-butyl1-((6-cyclopropyl-8-(2-fluoro-3-methoxy-3-oxopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(330 mg, 0.75 mmol) in DCM (10 mL) was added TFA (2 mL). The resultingreaction mixture was stirred at 50° C. for 2 h. The reaction mixture wasevaporated under reduced pressure to give1-((6-cyclopropyl-8-(2-fluoro-3-methoxy-3-oxopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid, which was used in next step without further purification. (350 mgcrude) as yellow oil. ESI-MS [M+H]⁺: 388.3.

Synthesis of Methyl3-(2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)-2-fluoropropanoate(I-224a)

To a solution of1-((6-cyclopropyl-8-(2-fluoro-3-methoxy-3-oxopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (350 mg crude from previous step) in dry DMF (5 mL) was added(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride(227 mg, 0.96 mmol), HATU (422 mg, 1.11 mmol) and DIPEA (287 mg, 2.2mmol). The reaction mixture was stirred at RT for 16 h. The reaction wasquenched with H₂O (50 mL) and extracted with ethyl acetate (50 mL×3).The combined organic layers were washed with brine (50 mL), dried overanhydrous sodium sulfate and concentrated in vacuo to give the residue,which was purified by Prep-TLC (DCM/MeOH=10/1) to afford methyl3-(2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)-2-fluoropropanoate(130 mg, yield: 30% over 2 steps) as a white solids. ESI-MS [M+H]⁺:569.3. Purity: 98.42 (214 nm), 97.32 (254 nm). ¹H NMR (400 MHz, DMSO-d6)δ 8.71 (t, J=5.5 Hz, 1H), 8.55 (s, 1H), 8.44 (d, J=2.4 Hz, 1H), 8.28 (d,J=1.3 Hz, 1H), 8.20 (d, J=7.4 Hz, 1H), 7.81 (s, 1H), 6.94 (s, 1H),6.80-6.73 (m, 1H), 5.74 (s, 2H), 5.69-5.52 (m, 1H), 4.70 (d, J=5.5 Hz,2H), 3.67 (s, 3H), 3.55-3.34 (m, 2H), 1.96-1.86 (m, 1H), 0.96-0.88 (m,2H), 0.72-0.63 (m, 2H).

Synthesis of3-(2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)-2-fluoropropanoicacid (I-224b)

To a solution of methyl3-(2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)-2-fluoropropanoate(100 mg, 0.176 mmol) in MeOH/H₂O (5 mL/5 mL) was added LiOH.H₂O (37 mg,0.88 mmol). The resulting reaction mixture was stirred at 50° C. for 5h. The solvent of the reaction mixture was evaporated under reducedpressure. The pH of the residue was acidified by HCl (1N) to around 2,and the yellow solid was precipitated. The mixture was filtered to givethe crude, which was purified by Prep-HPLC to give the3-(2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)-2-fluoropropanoicacid (50 mg, yield 50%) as a white solid. ESI-MS [M+H]+: 555.1. Purity:99.11 (214 nm), 100.00 (254 nm). ¹H NMR (400 MHz, DMSO-d6) δ 13.50 (s,1H), 8.71 (t, J=5.4 Hz, 1H), 8.56 (s, 1H), 8.44 (d, J=2.4 Hz, 1H), 8.27(d, J=1.0 Hz, 1H), 8.20 (d, J=7.4 Hz, 1H), 7.80 (s, 1H), 6.95 (s, 1H),6.81-6.71 (m, 1H), 5.75 (s, 2H), 5.47-5.40 (m, 1H), 4.70 (d, J=5.5 Hz,2H), 3.52-3.28 (m, 2H), 1.92-1.85 (m, 1H), 1.01-0.82 (m, 2H), 0.68-0.64(m, 2H).

Example 225

Synthesis of tert-butyl1-((6-cyclopropyl-8-(isoxazol-4-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate

To a solution of tert-butyl1-((8-bromo-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(300 mg, 0.72 mmol) and4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (210.6 mg, 1.08mmol) in DMF/H₂O (6 mL/0.6 mL) was added Pd(dppf)Cl₂ (52.63 mg, 0.072mmol), potassium fluoride (125.28 mg, 2.16 mmol). The resulting reactionmixture was stirred at 50° C. for 2 h under argon atmosphere. Thereaction mixture was diluted with EtOAC (100 mL), washed with H₂O (50mL). The organic layer was dried over sodium sulfate, evaporated to givethe residue, which was purified by silica gel chromatography(DCM/MeOH=15/1) to give the tert-butyl1-((6-cyclopropyl-8-(isoxazol-4-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(280 mg, 95%) as a yellow solid. ESI-MS [M+H]⁺: 407.2.

Synthesis of1-((6-cyclopropyl-8-(isoxazol-4-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicAcid

To a solution of tert-butyl1-((6-cyclopropyl-8-(isoxazol-4-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(280 mg, 0.68 mmol) in DCM (5 mL) was added TFA (393 mg, 3.45 mmol). Thereaction mixture was stirred at 50° C. for 3 h. The reaction mixture wasevaporated under reduced pressure to give1-((6-cyclopropyl-8-(isoxazol-4-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid, which was used in next step without further purification (300 mgcrude) as yellow oil. ESI-MS [M+H]⁺: 351.3.

Synthesis ofN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(isoxazol-4-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(I-225)

To a solution of1-((6-cyclopropyl-8-(isoxazol-4-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (300 mg, crude from previous step) in dry DMF (5 mL), was added(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride(194 mg, 0.82 mmol), HATU (393.3 mg, 1.03 mmol) and DIPEA (267 mg, 2.06mmol). The reaction mixture was stirred at RT for 5 h. The reaction wasquenched with H₂O (30 mL), extracted with ethyl acetate (50 mL×3). Thecombined organic layers were washed with brine (50 mL), dried overanhydrous sodium sulfate and concentrated in vacuo. The residue waspurified by Prep-TLC (DCM/MeOH=10/1) to affordN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(isoxazol-4-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(40 mg, yield: 11% over 2 steps) as a white solid. ESI-MS [M+H]⁺:532.10. Purity: 98.73 (214 nm), 99.42 (254 nm). ¹H NMR (400 MHz,DMSO-d6) δ 9.80 (s, 1H), 9.50 (s, 1H), 8.79-8.65 (m, 2H), 8.44 (d, J=2.1Hz, 1H), 8.38 (s, 1H), 8.20 (d, J=7.4 Hz, 1H), 7.91 (s, 1H), 7.52 (s,1H), 6.75 (t, J=6.9 Hz, 1H), 5.80 (s, 2H), 4.70 (d, J=5.4 Hz, 2H),2.00-1.93 (m, 1H), 1.01-0.90 (m, 2H), 0.83-0.76 (m, 2H).

Example 226

Synthesis of tert-butyl1-((6-cyclopropyl-8-(4-(ethoxycarbonyl)-1H-imidazol-1-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate

A mixture of tert-butyl1-((8-bromo-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(300 mg, 0.72 mmol), ethyl 1H-imidazole-4-carboxylate (150 mg, 1.07mmol), CuI (203 mg, 1.07 mmol),(1R,2R)—N1,N2-dimethylcyclohexane-1,2-diamine (152 mg, 1.07 mmol) andK₂CO₃ (199 mg, 1.44 mmol) in DMA (5 mL) was stirred at 140° C. under N₂for 7 h. The mixture was concentrated to give the crude, which waspurified by silica gel column chromatography (DCM/MeOH=15/1) to givetert-butyl1-((6-cyclopropyl-8-(4-(ethoxycarbonyl)-1H-imidazol-1-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(48 mg, yield: 14%) as yellow oil. ESI-MS [M+H]⁺: 478.1

Synthesis of1-((6-cyclopropyl-8-(4-(ethoxycarbonyl)-1H-imidazol-1-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicAcid

To a solution of tert-butyl1-((6-cyclopropyl-8-(4-(ethoxycarbonyl)-1H-imidazol-1-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(48 mg, 0.10 mmol) in DCM (5.0 mL) was added TFA (1.0 mL) at RT. Theresulting reaction mixture was stirred for 6 h. The mixture wasconcentrated to give1-((6-cyclopropyl-8-(4-(ethoxycarbonyl)-1H-imidazol-1-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid (55 mg,crude) as a yellow oil, which was used for the step directly withoutpurification. ESI-MS [M+H]⁺: 422.1.

Synthesis of Ethyl1-(2-((4-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methylcarbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)-1H-imidazole-4-carboxylate

A mixture of1-((6-cyclopropyl-8-(4-(ethoxycarbonyl)-1H-imidazol-1-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid (50 mg, crudefrom previous step),(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride(28.2 mg, 0.12 mmol), HATU (76.0 mg, 0.20 mmol) and DIPEA (64.5 mg, 0.5mmol) in DMF (2 mL) was stirred at RT for 16 h. Water (50 mL) was addedto the reaction, extracted with EtOAc (30 mL×3). The combined organiclayers were washed with brine, dried over Na₂SO₄, then concentrated. Thecrude was purified by Prep-TLC (DCM/MeOH=10/1) to give ethyl1-(2-((4-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methylcarbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)-1H-imidazole-4-carboxylate(40.0 mg, yield: 66% over 2 steps) as a white yellow solid. ESI-MS[M+H]⁺: 603.1.

Synthesis of1-(2-((4-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methylcarbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)-1H-imidazole-4-carboxylicacid (I-226)

A solution of ethyl1-(2-((4-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methylcarbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)-1H-imidazole-4-carboxylate(40.0 mg, 0.066 mmol) and LiOH.H₂O (13.9 mg, 0.33 mmol) in THF/MeOH/H₂O(1 mL/1 mL/1 mL) was stirred at RT for 2 h. The pH value was adjusted to3 by HCl (1 M), and then the mixture was concentrated to give the crude,which was purified by Prep-HPLC to give1-(2-((4-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methylcarbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)-1H-imidazole-4-carboxylicacid (7.4 mg, 19.5%) as a yellow solid. ESI-MS [M+H]⁺: 575.1. Purity:96.9 (214 nm), 95.9 (254 nm). ¹H NMR (400 MHz, DMSO-d₆) δ 8.74 (s, 1H),8.72-8.63 (m, 2H), 8.56 (s, 1H), 8.41 (s, 2H), 8.17 (d, J=7.3 Hz, 2H),7.95 (s, 1H), 7.42 (s, 1H), 6.72 (t, J=6.9 Hz, 1H), 5.79 (s, 2H), 4.67(d, J=5.4 Hz, 2H), 2.03-1.89 (m, 1H), 0.96-0.91 (m, 2H), 0.86-0.74 (m,2H).

Example 227

Synthesis of Ethyl 6-cyclopropylimidazo[1,2-a]pyridine-2-carboxylate

A solution of 5-cyclopropylpyridin-2-amine (1.4 g, 10.4 mmol) and ethyl3-bromo-2-oxopropanoate (3.05 g, 15.7 mmol) in DME (10 mL) was stirredat 80° C. overnight. The mixture was adjusted to pH=7 by adding Na₂CO₃solution and extracted with EtOAc (100 mL×3). The combined organiclayers were washed with brine, dried over Na₂SO₄ and concentrated. Theresidue was purified by silica gel chromatography (EA/PE=13:1) to giveethyl 6-cyclopropylimidazo[1,2-a]pyridine-2-carboxylate (614 mg, yield:26%) as a yellow solid. ESI-MS [M+H]⁺: 231.2

Synthesis of Ethyl3-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)-3-oxopropanoate

A solution of ethyl 6-cyclopropylimidazo[1,2-a]pyridine-2-carboxylate(424 mg, 1.84 mmol), ethyl acetate (811 mg, 9.2 mmol) and NaH (147 mg,3.68 mmol) in toluene/THF ((v/v)=1/2, 12 mL) was stirred at 70° C. for 1h. The mixture was quenched by saturated NH₄Cl solution (30 mL) andextracted by EtOAc (50 mL×3). The combined organic layers were washedwith brine, dried over Na₂SO₄ and concentrated to give crude ethyl3-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)-3-oxopropanoate (458 mg,crude) as a yellow solid which was used to the next step without furtherpurification. ESI-MS [M+H]⁺: 273.1.

Synthesis of Ethyl3-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)-3-hydroxypropanoate

A solution of ethyl3-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)-3-oxopropanoate (458 mg,crude) in EtOH (10 mL) was added NaBH₄ (70 mg, 1.85 mmol) slowly at 0°C. After the mixture was stirred at 0° C. for 45 min, the solution wasquenched by H₂O (30 mL) and extracted with EtOAc (50 mL×2). The combinedorganic layers were washed with brine, dried over Na₂SO₄ andconcentrated. The residue was purified by Prep-TLC (DCM/MeOH=10:1) togive ethyl3-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)-3-hydroxypropanoate (300 mg,yield: 59% over 2 steps) as a yellow solid. ESI-MS [M+H]⁺: 275.1.

Synthesis of Ethyl3-chloro-3-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)propanoate

To a solution of ethyl3-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)-3-hydroxypropanoate (200 mg,0.73 mmol) in DCM (6 mL) was added SOCl₂ (0.5 mL). The mixture wasstirred at RT overnight. The mixture was concentrated (200 mg, crude)and used into next step without further purification. ESI-MS [M+H]⁺:293.1.

Synthesis of Ethyl3-azido-3-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)propanoate

A mixture of ethyl3-chloro-3-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)propanoate (200 mg,crude from above step), NaN₃ (72 mg, 1.1 mmol) in DMF (5 mL) was stirredat RT overnight. The reaction mixture was diluted with H₂O (30 mL) andextracted with EtOAc (50 mL×3). The combined organic layers were washedwith brine, dried over Na₂SO₄ and concentrated. The residue was purifiedby column (DCM:MeOH=20:1) to give crude ethyl3-azido-3-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)propanoate (160 mg,yield: 73% over 2 steps) as a yellow solid. ESI-MS [M+H]⁺: 300.1.

Synthesis of tert-butyl1-(1-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)-3-ethoxy-3-oxopropyl)-1H-1,2,3-triazole-4-carboxylate

A mixture of crude ethyl3-azido-3-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)propanoate (160 mg,0.53 mmol), tert-butyl propiolate (101 mg, 0.8 mmol), CuSO₄ (26 mg, 0.16mmol) and sodium ascorbate (28 mg, 0.16 mmol) in t-BuOH/H₂O ((v/v)=2/1,9 mL) was stirred at RT overnight. The reaction mixture was diluted withH₂O (20 mL) then it was extracted with EtOAc (30 mL×3). The combinedorganic layers were washed with brine, dried over Na₂SO₄ andconcentrated. The residue was purified by Prep-TLC (DCM:MeOH=15:1) togive tert-butyl1-(1-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)-3-ethoxy-3-oxopropyl)-1H-1,2,3-triazole-4-carboxylate(100 mg, yield: 44%) as a yellow solid. ESI-MS [M+H]⁺: 426.2.

Synthesis of1-(1-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)-3-ethoxy-3-oxopropyl)-1H-1,2,3-triazole-4-carboxylicAcid

A solution of tert-butyl1-(1-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)-3-ethoxy-3-oxopropyl)-1H-1,2,3-triazole-4-carboxylate(100 mg, 0.24 mmol) in TFA (2 mL) and DCM (2 mL) was stirred at RT for 2h. The mixture was concentrated to give crude1-(1-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)-3-ethoxy-3-oxopropyl)-1H-1,2,3-triazole-4-carboxylicacid (100 mg, crude) which was used to the next step without furtherpurification. ESI-MS [M+H]⁺: 370.1.

Synthesis of Ethyl3-(4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)-3-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)propanoate(I-227a)

A mixture of crude1-(1-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)-3-ethoxy-3-oxopropyl)-1H-1,2,3-triazole-4-carboxylicacid (100 mg, crude from last step),(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride(52 mg, 0.22 mmol), HOBT (59 mg, 0.44 mmol), EDCI (84 mg, 0.44 mmol) andDIPEA (142 mg, 5.0 mmol) in DMF (6 mL) was stirred at RT for 4 h. Thereaction mixture was diluted with H₂O (50 mL) and extracted with EtOAc(50 mL×3). The combined organic layers were washed with brine, driedover Na₂SO₄ and concentrated. The residue was purified by Prep-TLC(DCM:MeOH=20:1) to give 1 ethyl3-(4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)-3-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)propanoate(66 mg, yield: 53%) as a white solid. ESI-MS [M+H]⁺: 551.2. Purity:98.80% (214 nm), 100% (254 nm). ¹H NMR (400 MHz, DMSO-d₆) δ 8.72-8.69(m, 2H), 8.44 (d, J=2.1 Hz, 1H), 8.33 (s, 1H), 8.21 (d, J=7.4 Hz, 1H),7.77 (s, 1H), 7.42 (d, J=9.3 Hz, 1H), 7.02 (d, J=9.4 Hz, 1H), 6.76 (t,J=6.8 Hz, 1H), 6.37-6.34 (m, 1H), 4.70 (d, J=5.4 Hz, 2H), 4.05-3.99 (m,2H), 3.62-3.51 (m, 2H), 1.95-1.89 (m, 1H), 1.10 (t, J=7.1 Hz, 3H),0.94-0.89 (m, 2H), 0.68-0.64 (m, 2H).

Synthesis of3-(4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)-3-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)propanoicacid (I-227b)

A solution of ethyl3-(4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)-3-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)propanoate(50 mg, 0.09 mmol) and LiOH.H₂O (97 mg, 2.32 mmol) in ethanol (1 mL),THF (4 mL) and H₂O (1 mL) was stirred at RT for 2 h. The mixture wasadjusted to pH-2 by adding HCl (1 M). The mixture was then extractedwith EtOAc (50 mL×3). The combined organic layers were concentrated andpurified by Prep-HPLC to get3-(4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)-3-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)propanoicacid (4.4 mg, yield: 9%) as a white solid. ESI-MS [M+H]⁺: 523.1. Purity:96.99% (214 nm), 97.64% (254 nm). ¹H NMR (400 MHz, DMSO-d₆) δ 8.58-8.53(m, 2H), 8.33 (d, J=2.0 Hz, 1H), 8.26 (s, 1H), 8.19 (s, 1H), 8.10 (d,J=7.4 Hz, 1H), 7.61 (s, 1H), 7.28 (d, J=9.3 Hz, 1H), 6.88 (d, J=9.4 Hz,1H), 6.65 (t, J=6.8 Hz, 1H), 6.19 (t, J=7.4 Hz, 1H), 4.59 (d, J=5.4 Hz,2H), 3.10-3.09 (m, 2H), 1.83-1.77 (m, 1H), 0.81-0.77 (m, 2H), 0.56-0.53(m, 2H).

Example 228

Synthesis of tert-butyl1-((6-cyclopropyl-8-((trimethylsilyl)ethynyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate

A solution of tert-butyl1-((8-bromo-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(210 mg, 0.5 mmol), ethynyltrimethylsilane (98 mg, 1.0 mmol),Pd(dppf)Cl₂ (37 mg, 0.05 mmol), CuI (10 mg, 0.05 mmol) and PPh₃ (875 mg,3.12 mmol) in i-Pr₂NH (1 mL) and toluene (3 mL) was degassed by N₂ andstirred at 80° C. (microwave) for 2 h. Water (30 mL) was added to thereaction, extracted with EtOAc (30 mL×3). The combined organic layerswere washed with brine, dried over Na₂SO₄, and concentrated to give thecrude which was purified with Prep-TLC (DCM/MeOH=15/1) to givetert-butyl1-((6-cyclopropyl-8-((trimethylsilyl)ethynyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(170 mg, 78%) as a yellow solid. ESI-MS [M+H]⁺: 436.2.

Synthesis of tert-butyl1-((6-cyclopropyl-8-ethynylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate

To a solution of tert-butyl1-((6-cyclopropyl-8-((trimethylsilyl)ethynyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(170 mg, 0.39 mmol) in THF was added TBAF (1.2 mL, 1 M solution in THF,1.2 mmol). The mixture was stirred at RT for another 1 h. The reactionwas quenched with saturated aqueous NH₄Cl (30 mL), extracted with EtOAc(30 mL×3). The combined organic layers were washed with brine, driedover Na₂SO₄, and concentrated to give the crude, which was purified byPrep-TLC (DCM/MeOH=20/1) to give tert-butyl1-((6-cyclopropyl-8-((trimethylsilyl)ethynyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(95 mg, yield: 66.9%) as a pale solid. ESI-MS [M+H]⁺: 364.1

Synthesis of1-((6-cyclopropyl-8-ethynylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicAcid

A solution of tert-butyl1-((6-cyclopropyl-8-ethynylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(50 mg, 0.14 mmol) in TFA (1 mL) and DCM (1 mL) was stirred at RT for 3h. The mixture was concentrated to give1-((6-cyclopropyl-8-ethynylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid, which was used to the next reaction without further purification(55 mg crude). ESI-MS [M+H]⁺: 308.1.

Synthesis ofN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-ethynylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(I-228)

A solution of crude1-((6-cyclopropyl-8-ethynylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (55 mg, crude from previous step),(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride(36 mg, 0.15 mmol), HOBT (38 mg, 0.28 mmol), EDCI (54 mg, 0.28 mmol) andDIPEA (91 mg, 0.7 mmol) in DMF (2 mL) was stirred at RT for 2 h. Water(20 mL) was added to the reaction, and the mixture was extracted byEtOAc (30 mL×3). The combined organic layers were washed with brine,dried over Na₂SO₄, and concentrated to give the crude, which waspurified by Prep-TLC (DCM/MeOH=20/1) to giveN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-ethynylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(21.8 mg, yield: 32% over 2 steps) as a white solid. ESI-MS [M+H]⁺:489.1. Purity: 97.56 (214 nm), 97.42 (254 nm) ¹H NMR (400 MHz, DMSO-d₆)δ 8.70 (t, J=5.4 Hz, 1H), 8.57 (s, 1H), 8.44-8.41 (m, 2H), 8.21 (d,J=7.4 Hz, 1H), 7.87 (s, 1H), 7.25 (d, J=1.5 Hz, 1H), 6.76 (t, J=7.2 Hz,1H), 5.76 (s, 2H), 4.71 (d, J=5.5 Hz, 2H), 4.50 (s, 1H), 1.93-1.90 (m,1H), 0.95-0.90 (m, 2H), 0.72-0.69 (m, 2H).

Example 229

Synthesis of Ethyl 6-bromobenzo[b]thiophene-2-carboxylate

To a solution of 4-bromo-2-fluorobenzaldehyde (1 g, 4.93 mmol) in DMSO(25 mL) was added ethyl 2-mercaptoacetate (651 mg, 5.42 mmol), followedby Et₃N (997 mg, 9.85 mmol). The reaction mixture was stirred at 80° C.for 3 h. The resulting mixture was poured into H₂O (20 mL) and extractedwith EtOAc (50 mL×3). The combined organic layers were concentrated togive the crude product, which was purified by silica gel chromatography(PE/EtOAc=40/1) to give the ethyl 6-bromobenzo[b]thiophene-2-carboxylateas a yellow solid (1.304 g, yield: 93%). ESI-MS [M+H]⁺: 284.7, 286.7.

Synthesis of Ethyl 6-cyclopropylbenzo[b]thiophene-2-carboxylate

To a solution of ethyl 6-bromobenzo[b]thiophene-2-carboxylate (1.304 g,4.57 mmol) in dioxane/H₂O (50 mL/5 mL) was added cyclopropylboronic acid(786 mg, 9.15 mmol), Pd(OAc)₂ (103 mg, 0.457 mmol), PCy₃ (256 mg, 0.915mmol) and K₃PO₄ (2.912 g, 13.7 mmol). The reaction mixture was stirredat 100° C. for 14 h under nitrogen. Then the mixture was concentrated invacuo. Water (40 mL) was added and the mixture was extracted with EtOAc(50 mL×3). The combined organic layers were concentrated to give thecrude product, which was purified by silica gel chromatography(PE/EtOAc=40/1) to give the ethyl6-cyclopropylbenzo[b]thiophene-2-carboxylate as a yellow solid (938 mg,yield: 83%). ESI-MS [M+H]⁺: 246.9.

Synthesis of (6-cyclopropylbenzo[b]thiophen-2-yl)methanol

To a solution ethyl ethyl 6-cyclopropylbenzo[b]thiophene-2-carboxylate(938 mg, 3.81 mmol) in THF (15 mL) was added LiAlH₄ (145 mg, 3.81 mmol)slowly. The mixture was stirred for 2 h at 0° C. Then the reaction wasquenched with H₂O (1 mL) and aqueous NaOH (10%, 1 mL) and the resultingmixture was filtered through celite. The filtrate was concentrated invacuo to give the crude product, which was purified by silica gelchromatography (PE/EtOAc=5/1) to give(6-cyclopropylbenzo[b]thiophen-2-yl)methanol (542 mg, yield: 76%) as ayellow solid. ESI-MS [M−OH]⁺: 187.1.

Synthesis of 2-(chloromethyl)-6-cyclopropylbenzo[b]thiophene

A solution of (6-cyclopropylbenzo[b]thiophen-2-yl)methanol (276 mg, 1.35mmol) in SOCl₂ (10 mL) was stirred at RT for 2 h. Then the mixture wasconcentrated in vacuo to give2-(chloromethyl)-6-cyclopropylbenzo[b]thiophene (300 mg, crude) as ayellow oil, which was used directly into the next step without furtherpurification.

Synthesis of 2-(azidomethyl)-6-cyclopropylbenzo[b]thiophene

A solution of 2-(chloromethyl)-6-cyclopropylbenzo[b]thiophene (300 mg,crude from above step) and NaN₃ (56 mg, 0.858 mmol) in DMF (5 mL) wasstirred at RT for 5 h. Water (20 mL) was added and extracted with EtOAc(30 mL×3). The combined organic layers were concentrated to give2-(azidomethyl)-6-cyclopropylbenzo[b]thiophene (195 mg, crude) as ayellow solid, which was used directly into the next step without furtherpurification.

Synthesis of Ethyl1-((6-cyclopropylbenzo[b]thiophen-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate

A solution 2-(azidomethyl)-6-cyclopropylbenzo[b]thiophene (195 mg, fromabove step), ethyl propiolate (167 mg, 1.7 mmol), CuSO₄ (42 mg, 0.17mmol) and sodium ascorbate (51 mg, 0.255 mmol) in t-BuOH (8 mL) and H₂O(8 mL) was stirred for 2 h at RT. Water (20 mL) was added and themixture was extracted with EtOAc (50 mL×3). The combined organic layerswere dried over Na₂SO₄, and concentrated to give the crude product,which was purified by silica gel chromatography (PE/EtOAc=3/1) to giveethyl1-((6-cyclopropylbenzo[b]thiophen-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(253 mg, yield: 53% over 3 steps) as a yellow solid. ESI-MS [M+Na]⁺:350.0

Synthesis of1-((6-cyclopropylbenzo[b]thiophen-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicAcid

A solution of ethyl1-((6-cyclopropylbenzo[b]thiophen-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(100 mg, 0.305 mmol) and LiOH.H₂O (13 mg, 0.305 mmol) in a mixed solventof THF/H₂O (4 mL/4 mL) was stirred at RT overnight. The pH value of themixture was adjusted to 5 and then concentrated to give1-((6-cyclopropylbenzo[b]thiophen-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (120 mg, crude) as a yellow solid, which was used directly in thenext step without further purification. ESI-MS [M+Na]⁺: 322.0.

Synthesis ofN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylbenzo[b]thiophen-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(I-229)

A mixture of1-((6-cyclopropylbenzo[b]thiophen-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (120 mg, crude from last step),(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride(82 mg, 0.35 mmol), HATU (221 mg, 0.58 mmol) and DIPEA (188 mg, 1.45mmol) in DMF (10 mL). The resulting mixture was stirred for 3 h at RT.The mixture was concentrated to remove DMF to give the crude product,which was purified by Prep-HPLC to giveN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylbenzo[b]thiophen-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(25 mg, yield: 17% over 2 steps) as a light yellow solid. ESI-MS [M+H]⁺:480.9. Purity: 99.65 (214 nm) 99.59 (254 nm). ¹H NMR (400 MHz, CDCl₃) δ8.09 (s, 2H), 7.63-7.48 (m, 3H), 7.48 (s, 1H), 7.11 (d, J=8.2 Hz, 1H),6.54 (t, J=4.6 Hz, 1H), 5.77 (s, 2H), 4.98 (d, J=4.6 Hz, 2H), 2.01-1.98(m, 1H), 1.02-0.99 (m, 2H), 0.75-0.77 (m, 2H).

Example 230

Synthesis of 2-(azidomethyl)-8-bromo-6-cyclopropylimidazo[1,2-a]pyridine

To a solution of8-bromo-2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine (1 g, 3.5mmol) in DMF (15 mL) was added NaN₃ (230 mg, 3.5 mmol). The resultingmixture was stirred at 50° C. for 24 h under nitrogen. H₂O (50 mL) wasadded to the reaction, extracted with EtOAc (50 mL×3). The combinedorganic layers were washed brine, dried over Na₂SO₄, concentrated invacuo to give2-(azidomethyl)-8-bromo-6-cyclopropylimidazo[1,2-a]pyridine (1.1 g,crude), which was used into next step without further purification.ESI-MS [M+H]⁺: 292.0.

Synthesis of tert-butyl1-((8-bromo-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate

To a solution2-(azidomethyl)-8-bromo-6-cyclopropylimidazo[1,2-a]pyridine (1.1 g,crude from previous step) and tert-butyl propiolate (860 mg, 6.8 mmol)in t-BuOH/H₂O (15 mL/15 mL) was added CuSO₄ (170 mg, 0.68 mmol), sodiumascorbate (180 mg, 1.02 mmol). The reaction mixture was stirred at RTfor 12 h. The mixture was concentrated in vacuo to give the crudeproduct, which was purified by silica gel chromatography (PE/EtOAc=1/2)to give tert-butyl1-((8-bromo-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(500 mg, 34% over 2 steps) as brown oil. ESI-MS [M+H]⁺: 417.7.

Synthesis of tert-butyl1-((6-cyclopropyl-8-(4-(methoxycarbonyl)-1H-pyrazol-1-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate

A solution of tert-butyl1-((8-bromo-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(440 mg, 1.05 mmol) methyl 1H-pyrazole-4-carboxylate (330 mg, 2.62mmol), CuI (20 mg, 0.105 mmol),(1R,2R)—N1,N2-dimethylcyclohexane-1,2-diamine (30 mg, 0.21 mmol) andK₂CO₃ (290 mg, 2.1 mmol) in toluene (5 mL) was degassed by N₂ for 10 minin in a sealed tube. The reaction mixture was stirred at 110° C. for 12h. The reaction was concentrated to remove the toluene. Water (30 mL)was added to the residue, and extracted with EtOAc (30 mL×3). Thecombined organic layers were washed with brine, dried over Na₂SO₄,concentrated in vacuo to give crude, which was purified with Prep-TLC(DCM/MeOH=15/1) to give the tert-butyl1-((6-cyclopropyl-8-(4-(methoxycarbonyl)-1H-pyrazol-1-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate (250 mg,51.4%) as a yellow solid. ESI-MS [M+H]⁺: 463.9

Synthesis of1-((6-cyclopropyl-8-(4-(methoxycarbonyl)-1H-pyrazol-1-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicAcid

A Tert-butyl1-((6-cyclopropyl-8-(4-(methoxycarbonyl)-1H-pyrazol-1-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(250 mg, 0.54 mmol) in HCl (5 mL, 4 M solution in EtOAc, 20 mmol) wasstirred at RT for 12 h. The mixture was concentrated to give1-((6-cyclopropyl-8-(4-(methoxycarbonyl)-1H-pyrazol-1-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid (270 mg, crude), which wasused into next step without further purification. ESI-MS [M+H]⁺: 407.9

Synthesis of Methyl1-(2-((4-(1-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)amino)vinyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)-1H-pyrazole-4-carboxylate

To a solution of1-((6-cyclopropyl-8-(4-(methoxycarbonyl)-1H-pyrazol-1-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid (270 mg crudefrom previous step) in DMF (5 mL) was added EDCI (155 mg, 0.81 mmol),HOBT (109 mg, 0.81 mmol), DIPEA (0.2 mL, 1.1 mmol) and(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride(153.4 mg, 0.65 mmol). The reaction mixture was stirred at RT for 12 h.The mixture was poured into 20 mL of H₂O, extracted with EtOAc (30mL×3). The combined organic layers were washed with brine, dried overNa₂SO₄, and concentrated to give the crude, which was purified byPrep-TLC (DCM/MeOH=10/1) to give methyl1-(2-((4-(1-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)amino)vinyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)-1H-pyrazole-4-carboxylate(46 mg, 14.5% over 2 steps) as a white solid. ESI-MS [M+H]⁺: 587.7

Synthesis of1-(2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)-1H-pyrazole-4-carboxylicacid (I-230)

To a solution of methyl1-(2-((4-(1-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)amino)vinyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)-1H-pyrazole-4-carboxylate(46 mg, 0.078 mmol) in THF/H₂O (2 mL/2 mL) was added LiOH (10 mg, 0.39mmol). The reaction mixture was stirred at RT for 12 h. The mixture wasconcentrated to give the crude product, which was purified by Prep-HPLCto give1-(2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)-1H-pyrazole-4-carboxylicacid (5 mg, yield: 11%) as a white solid. ESI-MS [M+H]⁺: 574.8. Purity:100 (214 nm) 100 (254 nm). ¹H NMR (400 MHz, DMSO-d₆) S=9.74 (s, 1H),8.71 (t, J=5.2 Hz, 1H), 8.59 (s, 1H), 8.45 (s, 1H), 8.43 (s, 1H), 8.21(s, 1H), 8.18 (d, J=3.6 Hz, 1H), 7.99 (s, 1H), 7.69 (s, 1H), 6.76 (t,J=6.8 Hz, 1H), 5.86 (s, 2H), 4.70 (d, J=5.2 Hz, 2H), 1.27-1.21 (m, 1H),0.97 (dd, J=14.8, 6.8 Hz, 2H), 0.74 (dd, J=10.4, 5.6 Hz, 2H).

Example 231

Synthesis of 4-methoxy-2-(trifluoromethyl)pyridine

To a solution of 2-(trifluoromethyl)pyridin-4-ol (5.8 g, 35.56 mmol) inDMF (40 mL) was added iodomethane (11.1 g, 78.23 mmol) and K₂CO₃ (6.05g, 43.74 mmol). Then the reaction mixture was stirred at 65° C. for 2 h.The mixture was treated with H₂O (100 mL) and extracted with EtOAc (70mL×3). The combined organic layers were washed with brine, dried overNa₂SO₄, concentrated to give 4-methoxy-2-(trifluoromethyl)pyridine as ayellow oil (3.5 g, yield: 55%) which was used in next step withoutfurther purification. ESI-MS [M+H]⁺: 178.1.

Synthesis of 1-amino-4-hydroxy-2-(trifluoromethyl)pyridin-1-ium

To a solution 4-methoxy-2-(trifluoromethyl)pyridine (3 g, 16.9 mmol) inDCM (50 mL) was added 0-(mesitylsulfonyl)hydroxylamine (3.6 g, 17 mmol)at RT. The mixture was stirred at RT for 14 h. The reaction mixture wasconcentrated to give the crude product, which was washed with tert-Butylmethyl ether (100 mL) and filtered to give1-amino-4-hydroxy-2-(trifluoromethyl)pyridin-1-ium (6 g, crude) as ayellow solid. ESI-MS [M+Na]⁺: 192.9.

Synthesis of dimethyl5-methoxy-7-(trifluoromethyl)pyrazolo[1,5-a]pyridine-2,3-dicarboxylate

To a solution of 1-amino-4-hydroxy-2-(trifluoromethyl)pyridin-1-ium (6g, crude from previous step) in DMF (25 mL) was added dimethylbut-2-ynedioate (5.39 g, 37.96 mmol) slowly, followed by K₂CO₃ (5.25 g,37.96 mmol). Then the resulting reaction mixture was stirred at RT for24 h. The reaction was poured into H₂O (100 mL), and the yellow solidwas precipitated. The mixture was filtrated, washed with H₂O (20 mL) anddried to give dimethyl5-methoxy-7-(trifluoromethyl)pyrazolo[1,5-a]pyridine-2,3-dicarboxylate(2.3 g, yield: 41.1% over 2 steps) as a yellow solid. ESI-MS [M+H]⁺:332.8.

Synthesis of5-hydroxy-7-(trifluoromethyl)pyrazolo[1,5-a]pyridine-2-carboxylic Acid

A mixture of dimethyl5-methoxy-7-(trifluoromethyl)pyrazolo[1,5-a]pyridine-2,3-dicarboxylate(2.3 g, 6.92 mmol) in H₂O (150 mL) was dissolved in con. H₂SO₄ (5 mL).And the resulting mixture was stirred at 120° C. for 14 h. The mixturewas poured into ice H₂O, and white solid was precipitated. The mixturewas filtrated and dried to give5-hydroxy-7-(trifluoromethyl)pyrazolo[1,5-a]pyridine-2-carboxylic acid(1.5 g crude) as a white solid, which was used into next step withoutfurther purification. ESI-MS [M+H]⁺: 246.7.

Synthesis of Methyl5-hydroxy-7-(trifluoromethyl)pyrazolo[1,5-a]pyridine-2-carboxylate

To a solution of5-hydroxy-7-(trifluoromethyl)pyrazolo[1,5-a]pyridine-2-carboxylic acid(1.5 g, crude from last step) in MeOH (30 mL) was added con. H₂SO₄ (1mL), then the mixture was stirred at 80° C. for 14 h. The reaction wasconcentrated to remove the solvent to give the residue, which was washedwith H₂O (50 mL) and extracted with EtOAc (50 mL×3). The combinedorganic layers were concentrated to give the crude product, which waspurified by silica gel chromatography (MeOH/DCM=1/10) to give methyl5-hydroxy-7-(trifluoromethyl)pyrazolo[1,5-a] pyridine-2-carboxylate (820mg, yield: 45% over 2 steps) as a yellow solid. ESI-MS [M+H]⁺: 260.8.

Synthesis of Methyl7-(trifluoromethyl)-5-(((trifluoromethyl)sulfonyl)oxy)pyrazolo[1,5-a]pyridine-2-carboxylate

To a solution of methyl5-hydroxy-7-(trifluoromethyl)pyrazolo[1,5-a]pyridine-2-carboxylate (820mg, 3.15 mmol) in DCM (30 mL) was added1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide(1.41 g, 3.94 mmol) and DIPEA (815 mg, 6.3 mmol), then the mixture wasstirred at 3 h. The solvent was removed to give the crude product whichwas purified silica gel chromatography (PE/EA=10/1) to give7-(trifluoromethyl)-5-(((trifluoromethyl)sulfonyl)oxy)pyrazolo[1,5-a]pyridine-2-carboxylate(970 mg, 78%) as a yellow solid. ESI-MS [M+H]⁺: 392.7.

Synthesis of Methyl5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1,5-a]pyridine-2-carboxylate

To a solution of7-(trifluoromethyl)-5-(((trifluoromethyl)sulfonyl)oxy)pyrazolo[1,5-a]pyridine-2-carboxylate(970 mg, 2.5 mmol) in Dioxane (20 mL) was added cyclopropylboronic acid(403 mg, 4.69 mmol), K₃PO₄ (1.49 g, 7.04 mmol) and Pd(dppf)Cl₂-DCM (115mg, 0.14 mmol). The resulting mixture was stirred at 90° C. for 14 h.Water (60 mL) was added to the reaction, and extracted with EtOAc (60mL×3). The combined organic layers were washed with brine, dried overNa₂SO₄, concentrated to give the crude product, which was purified withsilica gel chromatography (PE/EA=4/1) to give methyl5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1,5-a]pyridine-2-carboxylate(520 mg, yield: 73%) as a yellow oil. ESI-MS [M+H]⁺: 284.9.

Synthesis of(5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1,5-a]pyridin-2-yl)methanol

To a solution of methyl5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1,5-a]pyridine-2-carboxylate(555 mg, 1.95 mmol) in THF (20 mL) was added LiBH4 (85 mg, 3.91 mmol) at0° C. Then the reaction mixture was stirred at RT for 14 h. The reactionwas quenched with H₂O (50 mL) and extracted with EtOAc (50 mL×3). Thecombined organic layers were concentrated to give(5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1,5-a]pyridin-2-yl)methanol(500 mg crude) as yellow oil, which was used in next step withoutfurther purification. ESI-MS [M+H]⁺: 257.1.

Synthesis of2-(azidomethyl)-5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1,5-a]pyridine

To a solution of(5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1,5-a]pyridin-2-yl)methanol(250 mg crude from previous step) in THF (10 mL) was added DBU (164 mg,1.08 mmol) and DPPA (296 mg, 1.08 mmol). Then the resulting reactionmixture was stirred at RT for 14 h. Water (40 mL) was added to thereaction, and extracted with EtOAc (40 mL×3). The combined organiclayers were washed with brine, dried over Na₂SO₄, concentrated to givethe crude product, which was purified with silica gel chromatography(PE/EA=2/1) to give2-(azidomethyl)-5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1,5-a]pyridine(110 mg, yield: 40% over 2 steps) as a white solid. ESI-MS [M+H]⁺:281.8.

Synthesis of Ethyl1-((5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1,5-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate

To a solution of2-(azidomethyl)-5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1,5-a]pyridine(110 mg, 0.39 mmol) in t-BuOH/H₂O (4 mL/4 mL) was added ethyl propiolate(77 mg, 0.78 mmol), CuSO₄ (12.5 mg, 0.078 mmol) and sodium ascorbate (24mg, 0.12 mmol). Then the mixture was stirred at RT for 1 h. Thenconcentrated to give the crude product, which was purified with silicagel chromatography (PE/EA=2/1) to give ethyl1-((5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1,5-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(50 mg, yield: 34%) as a yellow solid. ESI-MS [M+H]⁺: 379.7.

Synthesis of1-((5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1,5-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicAcid

To a solution of ethyl 1-((5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1,5-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate (55 mg, 0.14mmol) in THF/H₂O (3 mL/3 mL) was added LiOH.H₂O (12 mg, 0.29 mmol). Thenthe mixture was stirred at RT for 14 h. The pH of the reaction wasadjusted by HCl (1N), and concentrated to give1-((5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1,5-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (70 mg, crude) as a yellow solid, which was used into next stepwithout further purification. ESI-MS [M+H]⁺: 351.7.

Synthesis ofN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1,5-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(I-231)

To a solution of1-((5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1,5-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (70 mg, crude from previous step) in DMF (5 mL) was added(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride(66 mg, 0.28 mmol), HATU (108 mg, 0.28 mmol) and DIPEA (110 mg, 0.85mmol). Then the mixture was stirred at RT for 1 h. The mixture waspoured into H₂O (20 mL), and solid was precipitated. The mixture wasfiltrated, washed with MeOH (30 mL), and then dried to giveN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1,5-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(10.5 mg, yield: 14% over 2 steps) as a white solid. ESI-MS [M+H]⁺:532.4. Purity: 100% (214 nm) 100% (254 nm). ¹H NMR (300 MHz, DMSO-d₆)S=8.71 (t, J=8.0 Hz, 1H), 8.61 (s, 1H), 8.42 (s, 1H), 8.19 (d, J=12.0Hz, 1H), 7.65 (s, 1H), 7.25 (s, 1H), 6.74 (t, J=12.0 Hz, 1H), 6.55 (s,1H), 5.87 (s, 2H), 4.69 (d, J=8.0 Hz, 2H), 2.10-2.04 (m, 1H), 1.04-1.00(m, 2H), 0.87-0.81 (m, 2H).

Example 232

Synthesis of 1-(tert-butyl) 2-ethyl 5-bromo-1H-indole-1,2-dicarboxylate

To a solution of ethyl 5-bromo-1H-indole-2-carboxylate (3 g, 11.2 mmol)in DMF (40 mL) was added NaH (672 mg, 60%, 16.8 mmol) at 0° C. andstirred for 1 h at this temperature. Then Boc₂O (4.9 g, 22.4 mmol) wasadded. The reaction mixture was stirred at RT for 16 h. The reaction wasquenched with H₂O (200 mL) and extracted with DCM (150 mL×3). Thecombined organic layers were concentrated to give the crude product,which was purified by silica gel chromatography (PE/EA=20/1) to give the1-(tert-butyl) 2-ethyl 5-bromo-1H-indole-1,2-dicarboxylate as a yellowsolid (4 g, yield: 97%). ESI-MS [M+Na]⁺: 390.0.

Synthesis of 1-(tert-butyl) 2-ethyl5-cyclopropyl-1H-indole-1,2-dicarboxylate

To a solution of 1-(tert-butyl) 2-ethyl5-bromo-1H-indole-1,2-dicarboxylate (4 g, 10.9 mmol) in toluene (50 mL)was added cyclopropylboronic acid (1.9 g, 21.8 mmol), Pd(OAc)₂ (246 mg,1.1 mmol), P(Cy)₃ (308 mg, 1.1 mmol) and K₃PO₄ (4.6 g, 21.8 mmol). Thereaction mixture was stirred at 100° C. for 5 h under nitrogen. Then themixture was concentrated in vacuo. Water (100 mL) was added to theresidue and extracted with DCM (150 mL×3). The combined organic layerswere concentrated to give the crude product, which was purified bysilica gel chromatography (PE/EA=20/1) to give the 1-(tert-butyl)2-ethyl 5-cyclopropyl-1H-indole-1,2-dicarboxylate as a yellow solid (3.1g, yield: 87%). ESI-MS [M+Na]⁺: 351.8.

Synthesis of Ethyl 5-cyclopropyl-1H-indole-2-carboxylate

A solution of 1-(tert-butyl) 2-ethyl5-cyclopropyl-1H-indole-1,2-dicarboxylate (3.1 g, 9.4 mmol) in HCl inEtOH (33%, 45 mL) was stirred at RT for 6 h. The mixture was thenconcentrated and purified by silica gel chromatography (PE/EA=10/1) togive ethyl 5-cyclopropyl-1H-indole-2-carboxylate (2.1 g, yield: 96%) asa yellow solid. ESI-MS [M+H]⁺: 230.0

Synthesis of (5-cyclopropyl-1H-indol-2-yl)methanol

To a solution of ethyl 5-cyclopropyl-1H-indole-2-carboxylate (1.1 g, 4.8mmol) in THF (15 mL) was added LiAlH₄ (273 mg, 7.2 mmol) slowly at 0° C.The reaction mixture was stirred at RT for 6 h. The reaction wasquenched by H₂O (0.5 mL), 10% NaOH (0.5 mL) and H₂O (1.5 mL), themixture was then filtered through celite and filtrate was concentratedto give the crude product, which was purified by silica gelchromatography (PE/EA=1/1) to give (5-cyclopropyl-1H-indol-2-yl)methanol(780 mg, yield: 86%) as a white solid. ESI-MS [M+H]⁺: 187.9.

Synthesis of 2-(azidomethyl)-5-cyclopropyl-1H-indole

To a solution of (5-cyclopropyl-1H-indol-2-yl)methanol (780 mg, 4.1mmol) and DPPA (1.2 g, 4.5 mmol) in toluene (15 mL) was added DBU (760mg, 4.9 mmol) at 0° C. The reaction mixture was stirred at RT for 16 h.Water (40 mL) was added and the mixture was extracted with DCM (50mL×2). The combined organic layers were concentrated and purified bysilica gel chromatography (PE/EA=20/1) to give2-(azidomethyl)-5-cyclopropyl-1H-indole (570 mg, yield: 65%) as a brownoil. ESI-MS [M+H]⁺: 212.9

Synthesis of Ethyl1-((5-cyclopropyl-1H-indol-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate

A mixture of 2-(azidomethyl)-5-cyclopropyl-1H-indole (570 mg, 2.7 mmol),ethyl propiolate (392 mg, 4.0 mmol), CuSO₄.5H₂O (135 mg, 0.54 mmol),sodium ascorbate (158 mg, 0.8 mmol) in t-BuOH/H₂O (8 mL/8 mL) wasstirred at RT for 16 h. Water (30 mL) was added and extracted with EtOAc(50 mL×3). The combined organic layers concentrated in vacuo to give thecrude product, which was purified by silica gel chromatography(PE/EA=1/4) to give ethyl1-((5-cyclopropyl-1H-indol-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(400 mg, yield: 48%) as a yellow solid. ESI-MS [M]⁺: 311.1

Synthesis of1-((5-cyclopropyl-1H-indol-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicAcid

A mixture of ethyl1-((5-cyclopropyl-1H-indol-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(400 mg, 1.3 mmol), NaOH (103 mg, 2.6 mmol) in THF/EtOH/H₂O (5 mL/5 mL/5mL) was stirred at RT for 0.5 h. The mixture was acidified with 1N HClsolution to pH around 5, then concentrated to give1-((5-cyclopropyl-1H-indol-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (340 mg, crude) as a white solid. ESI-MS [M+Na]⁺: 305.0.

Synthesis ofN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((5-cyclopropyl-1H-indol-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(I-232)

A mixture of1-((5-cyclopropyl-1H-indol-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic(34 mg, crude), (7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanaminehydrochloride (35 mg, 0.14 mmol), EDCI (29 mg, 0.15 mmol), HOBT (20 mg,0.15 mmol), DIPEA (45 mg, 0.35 mmol) in DMF (3 mL) was stirred at RT for16 h. Water (20 mL) was added and extracted with EtOAc (50 mL×3), thecombined organic layers were concentrated to give the crude product,which was purified by Prep-TLC to giveN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((5-cyclopropyl-1H-indol-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(17 mg) as a white solid. ESI-MS [M+H]⁺: 463.8. Purity: 97.38% (214 nm),98.22 (254 nm). ¹H NMR (400 MHz, DMSO-d₆) δ 11.15 (s, 1H), 8.70 (s, 1H),8.55 (s, 1H), 8.43 (s, 1H), 8.20 (d, J=7.4 Hz, 1H), 7.23-7.20 (m, 2H),6.84 (d, J=8.3 Hz, 1H), 6.75 (t, J=6.8 Hz, 1H), 6.37 (s, 1H), 5.75 (s,2H), 4.70 (d, J=5.2 Hz, 2H), 1.96-1.92 (m, 1H), 0.88-0.86 (m, 2H),0.60-0.59 (m, 2H).

Example 233

Synthesis of Ethyl 5-cyclopropyl-1-methyl-1H-indole-2-carboxylate

To a solution of ethyl 5-cyclopropyl-1H-indole-2-carboxylate (1 g, 4.3mmol) in DMF (15 mL) was added NaH (256 mg, 60%, 6.4 mmol) at 0° C. andstirred for 1 h at this temperature. Then MeI (1.2 g, 8.6 mmol) wasadded. The reaction mixture was stirred at RT for 16 h. The reaction wasquenched by H₂O (100 mL) and extracted with DCM (100 mL×3). The combinedorganic layers were concentrated to give the crude product, which waspurified by silica gel chromatography (PE/EA=20/1) to give the ethyl5-cyclopropyl-1-methyl-1H-indole-2-carboxylate as a yellow solid (900mg, yield: 84%). ESI-MS [M+Na]⁺: 244.0.

Synthesis of (5-cyclopropyl-1-methyl-1H-indol-2-yl)methanol

To a solution of ethyl 5-cyclopropyl-1-methyl-1H-indole-2-carboxylate(900 mg, 3.7 mmol) in THF (15 mL) was added LiAlH₄ (211 mg, 5.5 mmol)slowly at 0° C. The reaction mixture was stirred at RT for 6 h. Thereaction was quenched by H₂O (0.5 mL) and 10% NaOH (0.5 mL) and H₂O (1.5mL). The mixture was filtered through celite and filtrate wasconcentrated to give the crude product, which was purified by silica gelchromatography (PE/EA=1/1) to give(5-cyclopropyl-1-methyl-1H-indol-2-yl)methanol (600 mg, yield: 80%) as awhite solid. ESI-MS [M+H]⁺: 202.2.

Synthesis of 2-(azidomethyl)-5-cyclopropyl-1-methyl-1H-indole

To a solution of (5-cyclopropyl-1-methyl-1H-indol-2-yl)methanol (600 mg,3 mmol) and DPPA (907 mg, 3.3 mmol) in toluene (15 mL) was added DBU(547 mg, 3.6 mmol) at 0° C. The reaction mixture was stirred at RT for16 h. Water (40 mL) was added and the mixture was extracted with DCM (50mL×3). The combined organic layers were concentrated and purified bysilica gel chromatography (PE/EA=20/1) to give2-(azidomethyl)-5-cyclopropyl-1-methyl-1H-indole (450 mg, yield: 67%) asa white solid. ESI-MS [M+H]⁺: 227.1

Synthesis of Ethyl1-((5-cyclopropyl-1-methyl-1H-indol-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate

A mixture of 2-(azidomethyl)-5-cyclopropyl-1-methyl-1H-indole (450 mg,2.0 mmol), ethyl propiolate (252 mg, 3.0 mmol), CuSO₄.5H₂O (100 mg, 0.4mmol), sodium ascorbate (60 mg, 0.6 mmol) in t-BuOH/H₂O (10 mL/10 mL)was stirred at RT for 16 h. Water (30 mL) was added and extracted withEtOAc (50 mL×3). The combined organic layers were concentrated to givethe crude product, which was purified by silica gel chromatography(PE/EA=1/1) to give ethyl1-((5-cyclopropyl-1-methyl-1H-indol-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(380 mg, yield: 59%) as a white solid. ESI-MS [M+H]⁺: 325.1

Synthesis of1-((5-cyclopropyl-1-methyl-1H-indol-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicAcid

A mixture of ethyl1-((5-cyclopropyl-1-methyl-1H-indol-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(380 mg, 1.2 mmol), NaOH (95 mg, 2.6 mmol) in THF/EtOH H₂O (3 mL/3 mL/3mL) was stirred at RT for 0.5 h. The mixture was acidified with 1N HClsolution then concentrated to give the crude product1-((5-cyclopropyl-1-methyl-1H-indol-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (400 mg, crude) as a white solid. ESI-MS [M+H]⁺: 297.1

Synthesis ofN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((5-cyclopropyl-1-methyl-1H-indol-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(I-233)

A mixture of1-((5-cyclopropyl-1-methyl-1H-indol-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (30 mg, crude from last step),(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride(23.5 mg, 0.1 mmol), EDCI (21 mg, 0.11 mmol), HOBT (15 mg, 0.11 mmol),DIPEA (32.2 mg, 0.25 mmol) in DMF (3 mL) was stirred at RT for 16 h.Water (20 mL) was added and extracted with EtOAc (50 mL×3), the combinedorganic layers were concentrated to give the crude product, which waspurified by Prep-TLC to giveN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((5-cyclopropyl-1-methyl-1H-indol-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(9 mg) as a white solid. ESI-MS [M+H]⁺: 477.6. Purity: 98.79% (214 nm),98.35% (254 nm). ¹H NMR (400 MHz, DMSO-d₆) δ 8.71 (s, 1H), 8.52 (s, 1H),8.44 (s, 1H), 8.20 (d, J=7.4 Hz, 1H), 7.30 (d, J=8.5 Hz, 1H), 7.23 (s,1H), 6.91 (d, J=8.3 Hz, 1H), 6.75 (t, J=6.8 Hz, 1H), 6.42 (s, 1H), 5.89(s, 2H), 4.69 (d, J=5.0 Hz, 2H), 3.67 (s, 3H), 1.99-1.92 (m, 1H),0.90-0.87 (m, 2H), 0.62-0.60 (m, 2H).

Example 234

Synthesis of Ethyl 5-bromobenzo[b]thiophene-2-carboxylate

To a solution of 4-chloro-2-fluorobenzaldehyde (2 g, 12.6 mmol) andethyl 2-mercaptoacetate (1.58 g, 12.6 mmol) in EtOH (40 mL) was addedNa₂CO₃ (1.58 g, 15.1 mmol). The reaction mixture was stirred at refluxfor 14 h. Then the mixture was concentrated in vacuo. Water (30 mL) wasadded and the mixture was extracted with DCM (50 mL×3). The combinedorganic layers were concentrated to give the crude product, which waspurified by silica gel chromatography (PE/EtOAc=1/1) to give the ethyl5-bromobenzo[b]thiophene-2-carboxylate as a yellow solid (2.36 g, yield:78%). ESI-MS [M+H]⁺: 240.9.

Synthesis of (6-cyclopropylbenzofuran-2-yl)methanol

To a stirring solution of ethyl 6-chlorobenzo[b]thiophene-2-carboxylate(1.2 g, 5 mmol) in dry THF (25 mL) was added portion-wise of LiAlH₄ (570mg, 15 mmol) under 0° C. The resulting mixture was stirred at 0° C. for1 h. The reaction was quenched sequentially with H₂O (1 mL), 15% NaOH (1mL) and H₂O (3 mL). The resulting mixture was filtered through celiteand the filtrate was concentrated to give the crude product(6-chlorobenzo[b]thiophen-2-yl)methanol (970 mg, crude) as a lightyellow oil, which was used for the next step directly. ESI-MS [M+H]⁺:181.0

Synthesis of 2-(azidomethyl)-6-chlorobenzo[b]thiophene

To a solution of (6-cyclopropylbenzofuran-2-yl)methanol (970 mg, crudefrom last step) and DPPA (1.61 mg, 5.9 mmol) in dry THF (15 mL) at 0° C.was added DBU (888 mg, 5.9 mmol). The resulting mixture was stirred atRT overnight. Water (50 mL) was added and extracted with EtOAc (50mL×3). The combined organic layers were concentrated and purified byflash silica gel column chromatography (DCM/MeOH=20/1) to give theproduct 2-(azidomethyl)-6-chlorobenzo[b]thiophene (862 mg, 78% over 2steps) as a light yellow oil. ESI-MS [M+H]⁺: 224.1.

Synthesis of Ethyl1-((6-chlorobenzo[b]thiophen-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate

To a solution of 2-(azidomethyl)-6-chlorobenzo[b]thiophene (862 mg, 3.8mmol) in t-BuOH (10 mL) and H₂O (10 mL) was added sequentially ofCuSO₄-5H₂O (188 mg, 0.76 mmol), L(+)-Ascorbic acid sodium salt (193 mg,0.95 mmol) and ethyl propiolate (724 mg, 7.49 mmol). The resultingmixture was stirred at RT for 15 h. The reaction mixture wasconcentrated to get the crude product, which was purified by flashcolumn chromatography (DCM/MeOH=20/1) to give the product ethyl1-((6-chlorobenzo[b]thiophen-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(1 g, 82%) as an off-yellow oil. ESI-MS [M+H]⁺: 328.2

Synthesis of1-((6-chlorobenzo[b]thiophen-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicAcid

A solution of ethyl1-((6-chlorobenzo[b]thiophen-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (1 g, 3 mmol) and LiOH.H₂O (467 mg, 11.4 mmol) in a mixed solventof MeOH/H₂O (15 mL/15 mL) was stirred at RT for 2 h. The volatiles wasremoved in vacuo and the aqueous phase was acidified to pH 4-5 with 2NHCl. The precipitate was collected and dried to give the product1-((6-chlorobenzo[b]thiophen-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (720 mg, 80% yield) as a yellow solid. ESI-MS [M+H]⁺: 300.1

Synthesis ofN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-chlorobenzo[b]thiophen-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(I-234)

To a solution of1-((6-cyclopropylbenzofuran-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (90 mg, 0.3 mmol),(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride(70 mg, 0.3 mmol), EDCI (86 mg, 0.45 mmol) and HOBT (60 mg, 0.45 mmol)in DMF (5 mL) was added DIPEA (77 mg, 0.6 mmol). The resulting mixturewas stirred at RT for 15 h. Water (20 mL) was added and extracted withEtOAc (50 mL×3), the combined organic layers were concentrated andpurified by Prep-TLC to give productN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-chlorobenzo[b]thiophen-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(9 mg, 6% yield) as an off-white solid. ESI-MS [M+H]⁺: 474.5. Purity:97.25% (214 nm), 97.53% (254 nm). ¹H NMR (400 MHz, DMSO-d₆) δ 8.75 (s,1H), 8.69 (s, 1H), 8.44 (s, 1H), 8.21 (d, J=7.3 Hz, 1H), 8.11 (s, 1H),7.86 (d, J=8.5 Hz, 1H), 7.49 (s, 1H), 7.41 (d, J=8.4 Hz, 1H), 6.76 (t,J=6.9 Hz, 1H), 6.00 (s, 2H), 4.70 (d, J=5.2 Hz, 2H).

Example 235

Synthesis of Methyl 6-cyclopropyl-1H-indole-2-carboxylate

A mixture of methyl 6-bromo-1H-indole-2-carboxylate (100 mg, 0.39 mmol),cyclopropylboronic acid (66 mg, 0.78 mmol), Pd(OAc)₂ (9 mg, 0.04 mmol),SPhos (16 mg, 0.04 mmol) and K₃PO₄ (76 mg, 1.36 mmol) in Tol/H₂O (2 mL/1mL) was stirred at 90° C. for 4 h. Water (15 mL) was added and extractedwith EtOAc (50 mL), the combined organic layer were concentrated andpurified by silica gel chromatography (PE/EA=10/1) to give methyl6-cyclopropyl-1H-indole-2-carboxylate (60 mg, yield: 72%) as a whitesolid. ESI-MS [M+H]⁺: 216.1.

Synthesis of (6-cyclopropyl-1H-indol-2-yl)methanol

To a solution of methyl 6-cyclopropyl-1H-indole-2-carboxylate (60 mg,0.28 mmol) in THF (1 mL) was added LiAlH₄ (13 mg, 0.34 mmol) in dry THF(2 mL) dropwise at 0° C. The reaction mixture was stirred at RT for 2 h,quenched with H₂O at 0° C., filtered, and the filtrate was extractedwith EtOAc (30 mL×3). The combined organic layers were washed by brine(10 mL), dried over Na₂SO₄, concentrated and purified by silica gelchromatography (PE/EA=2/1) to give (6-cyclopropyl-1H-indol-2-yl)methanol(50 mg, yield: 96%) as a white solid. ESI-MS [M+H]⁺: 188.1.

Synthesis of 2-(azidomethyl)-6-cyclopropyl-1H-indole

To a solution of (6-cyclopropyl-1H-indol-2-yl)methanol (300 mg, 1.6mmol) and DPPA (1 g, 3.8 mmol) in dry CH₂Cl₂ (6 mL) was added DBU (580mg, 3.8 mmol) dropwise at 0° C. The reaction mixture was stirred at 0°C. for 2 h and then at RT for 16 h. Water (30 mL) was added andextracted with CH₂Cl₂ (60 mL×3), the organic layers were concentratedand purified by silica gel chromatography (PE/EA=10/1) to give2-(azidomethyl)-6-cyclopropyl-1H-indole (230 mg, yield: 68%) as yellowoil. ESI-MS [M+H]⁺: 213.1

Synthesis of Ethyl1-((6-cyclopropyl-1H-indol-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate

A mixture of 2-(azidomethyl)-6-cyclopropyl-1H-indole (230 mg, 1.1 mmol),ethyl propiolate (324 mg, 3.3 mmol), CuSO₄ (18 mg, 0.11 mmol) and sodiumascorbate (20 mg, 0.11 mmol) in H₂O/t-BuOH (3 mL/3 mL) was stirred at RTfor 4 h. Water (20 mL) was added then extracted with EtOAc (50 mL*3),the combined organic layers were concentrated and purified by silica gelchromatography (DCM/MeOH=8/1) to give ethyl1-((6-cyclopropyl-1H-indol-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(300 mg, yield: 89%) as a white solid. ESI-MS [M+Na]⁺: 333.1.

Synthesis of1-((6-cyclopropyl-1H-indol-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicAcid

A mixture of ethyl1-((6-cyclopropyl-1H-indol-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(300 mg, 0.97 mmol) and LiOH.H₂O (80 mg, 1.9 mmol) in THF/EtOH/H₂O (2mL/2 mL/1 mL) was stirred at 50° C. for 1 h. Most of the solvent wasremoved and the residue was diluted with H₂O (5 mL), the pH value ofmixture was adjusted to 4-5 by adding HCl aqueous (1 M). The precipitatewas collected and dried to give1-((6-cyclopropyl-1H-indol-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (200 mg, yield: 73%) as a white solid. ESI-MS [M+H]⁺: 283.1.

Synthesis ofN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-1H-indol-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(I-235)

A mixture of1-((6-cyclopropyl-1H-indol-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (56 mg, 0.2 mmol),(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride(57 mg, 0.24 mmol), HOBT (54 mg, 0.4 mmol), EDCI (77 mg, 0.4 mmol) andDIPEA (129 mg, 1.0 mmol) in DMF (4 mL) was stirred at RT for 16 h. Water(20 mL) was added and extracted with EtOAc (30 mL×3), the combinedorganic layers were washed by brine (20 mL), dried over Na₂SO₄,concentrated and purified by prep-HPLC to giveN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-1H-indol-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(40 mg, yield: 43%) as a white solid. ESI-MS [M+H]⁺: 464.1. Purity:90.87 (214 nm), 95.46 (254 nm). ¹H NMR (400 MHz, DMSO-d₆) δ 11.11 (s,1H), 8.71 (t, J=5.5 Hz, 1H), 8.54 (s, 1H), 8.43 (d, J=2.4 Hz, 1H), 8.20(d, J=7.4 Hz, 1H), 7.36 (d, J=8.2 Hz, 1H), 7.03 (s, 1H), 6.77-6.71 (m,2H), 6.40 (d, J=1.2 Hz, 1H), 5.75 (s, 2H), 4.69 (d, J=5.5 Hz, 2H),1.98-1.94 (m, 1H), 0.93-0.88 (m, 2H), 0.64-0.60 (m, 2H).

Example 236

Synthesis of 5-bromo-2-(chloromethyl)-1H-benzo[d]imidazole

A mixture of 4-bromobenzene-1,2-diamine (2.0 g, 10.8 mmol) and2-chloroacetic acid (1.5 g, 16.2 mmol) in HCl (2 M, 20 mL) was stirredat 100° C. for 16 h. The pH value of the reaction mixture was adjustedto 7-8 with aqueous NaOH and extracted with EtOAc (100 mL×3). Thecombined organic layers were concentrated to give5-bromo-2-(chloromethyl)-1H-benzo[d]imidazole (2.2 g, crude) as a blacksolid which was used into next step without purification. ESI-MS [M+H]⁺:244.9.

Synthesis of 2-(azidomethyl)-5-bromo-1H-benzo[d]imidazole

A solution of 5-bromo-2-(chloromethyl)-1H-benzo[d]imidazole (1.0 g,crude from last step) and NaN₃ (0.4 g, 6.12 mmol) in DMF (10 mL) wasstirred at 25° C. for 2 h, H₂O (50 mL) was added and extracted withEtOAc (50 mL×3). The combined organic layers were concentrated to give2-(azidomethyl)-5-bromo-1H-benzo[d]imidazole (0.8 g, crude) as a yellowsolid. ESI-MS [M+H]⁺: 252.0.

Synthesis of tert-butyl1-((5-bromo-1H-benzo[d]imidazol-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate

A solution of 2-(azidomethyl)-5-bromo-1H-benzo[d]imidazole (0.8 g, crudefrom last step), tert-butyl propiolate (0.5 g, 3.8 mmol), CuSO₄ (0.1 g,0.6 mmol), sodium ascorbate (0.12 g, 0.6 mmol) in t-BuOH (10 mL) and H₂O(10 mL) was stirred at 25° C. for 16 h. Water (30 mL) was added andextracted with EtOAc (50 mL×3), the combined organic layers wereconcentrated and purified by silica gel chromatography (DCM/MeOH=20/1)to give tert-butyl1-((5-bromo-1H-benzo[d]imidazol-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(0.5 g) as a yellow solid. ESI-MS [M+H]⁺: 378.1.

Synthesis of tert-butyl1-((5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate

To a solution of tert-butyl1-((5-bromo-1H-benzo[d]imidazol-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(0.5 g, 1.32 mmol) in dry THF (15 mL) was added NaH (63 mg, 1.58 mmol).The mixture was stirred at 0° C. for 20 min. Then SEMCl (0.24 g, 1.45mmol) was added and stirred at RT for 1 h. The mixture was quenched withH₂O (50 mL), extracted with EtOAc (60 mL×3). The combined organic layerswere washed with brine, dried over Na₂SO₄, filtered and concentrated togive the crude, which was purified by silica gel chromatography(DCM/MeOH=20/1) to give tert-butyl1-((5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(0.25 g, yield: 37.3%) as a yellow solid. ESI-MS [M+H]⁺: 510.1.

Synthesis of tert-butyl1-((5-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate

A solution of tert-butyl1-((5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(0.25 g, 0.5 mmol), cyclopropylboronic acid (0.09 g, 1.0 mmol), K₃PO₄(0.37 g, 1.75 mmol), SPhos (0.06 g, 0.15 mmol) and Pd(OAc)₂ (0.03 g,0.08 mmol). in a mixed solvent of toluene (30 mL) and H₂O (3 mL) wasstirred at 90° C. for 16 h under N₂, Water (100 mL) was added andextracted with EtOAc (50 mL×3). The combined organic layers wereconcentrated and purified by silica gel chromatography (DCM/MeOH=60/1)to give tert-butyl1-((5-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(0.2 g, yield: 86.0%) as a yellow solid. ESI-MS [M+H]⁺: 470.2.

Synthesis of1-((5-cyclopropyl-1H-benzo[d]imidazol-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicAcid

To a solution of tert-butyl1-((5-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(0.2 g, 0.4 mmol) in DCM (9 mL) was added TFA (3 mL). The mixture wasstirred at 25° C. for 5 h. The solvent was removed to give the crude1-((5-cyclopropyl-1H-benzo[d]imidazol-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (0.13 g, crude) as a black solid which was used into next stepwithout purification. ESI-MS [M+H]⁺: 284.1.

Synthesis ofN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((5-cyclopropyl-1H-benzo[d]imidazol-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(I-236)

To a solution of1-((5-cyclopropyl-1H-benzo[d]imidazol-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (0.13 g, crude from last step) was added(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride(0.1 g, 0.42 mmol), HATU (0.2 g, 0.53 mmol) and DIPEA (0.14 g, 1.05mmol) in DMF (5 mL). The mixture was stirred at 25° C. for 3 h. Thesolvent was removed to give the crude and purified by Prep-HPLC to giveN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((5-cyclopropyl-1H-benzo[d]imidazol-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(35 mg, yield: 19% over 2 steps) as a pale solid. ESI-MS [M+H]⁺: 465.1.Purity: 96.17% (214 nm), 100.00% (254 nm). ¹H NMR (400 MHz, DMSO-d₆) δ8.77 (t, J=5.4 Hz, 1H), 8.66 (s, 1H), 8.45 (d, J=2.4 Hz, 1H), 8.21 (d,J=7.4 Hz, 1H), 7.42 (d, J=8.4 Hz, 1H), 7.23 (s, 1H), 6.95 (dd, J=8.4,1.5 Hz, 1H), 6.81-6.71 (m, 1H), 5.92 (s, 2H), 4.71 (d, J=5.5 Hz, 2H),1.96-2.05 (m, 2H), 0.97-0.89 (m, 2H), 0.69-0.62 (m, 2H).

Example 237

Synthesis of1-((8-(3-amino-2,2-dimethyl-3-oxopropyl)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide

To a solution of3-(2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-pyrazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)-2,2-dimethylpropanoicacid (120 mg, 0.21 mmol), NH₄Cl (113 mg, 2.1 mmol), EDCI (61 mg, 0.32mmol) and HOBT (43 mg, 0.32 mmol) in DMF (10 mL) was added DIPEA (135mg, 1.05 mmol). The resulting reaction was stirred at RT for 12 h. H₂O(25 mL) was added to the reaction, extracted with EtOAc (15 mL×3). Thecombined organic layers were washed with brine, dried over Na₂SO₄,concentrated in vacuo to give the crude, which was purified withPrep-TLC (DMC/MeOH=10/1) to give the1-((8-(3-amino-2,2-dimethyl-3-oxopropyl)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide(80 mg, yield: 67.6%) as a light yellow solid. ESI-MS [M+H]⁺: 563.2.

Synthesis ofN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((8-(2-cyano-2-methylpropyl)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(I-237)

To a solution of1-((8-(3-amino-2,2-dimethyl-3-oxopropyl)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide(80 mg, 0.14 mmol) in POCl₃ (5 mL) was stirred at 60° C. for 0.5 h. Themixture was evaporated. The pH of the residue was adjust 8 by aqueousNaHCO₃, extracted with EtOAc (25 mL×3). The combined organic layers werewashed with brine, dried over Na₂SO₄, concentrated in vacuo to give thecrude, which was purified with Prep-TLC (DMC/MeOH=15/1) to give theN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((8-(2-cyano-2-methylpropyl)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(40 mg, yield: 52%) as a white solid. ESI-MS [M+H]⁺: 546.2. Purity:99.8% (214 nm), 100.0% (254 nm). ¹H NMR (400 MHz, DMSO-d₆) δ 8.67 (t,J=5.3 Hz, 1H), 8.50 (s, 1H), 8.44 (d, J=2.1 Hz, 1H), 8.32 (s, 1H), 8.21(d, J=7.4 Hz, 1H), 7.82 (s, 1H), 6.95 (s, 1H), 6.76 (t, J=6.9 Hz, 1H),5.73 (s, 2H), 4.69 (d, J=5.4 Hz, 2H), 3.13 (s, 2H), 1.97-1.87 (m, 1H),1.29 (s, 6H), 0.97-0.88 (m, 2H), 0.72-0.63 (m, 2H).

Example 238

Synthesis ofN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(2-methyl-2-(2H-tetrazol-5-yl)propyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(I-238)

To a solution ofN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((8-(2-cyano-2-methylpropyl)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(20 mg, 0.037 mmol) in n-BuOH (3 mL) was added NaN₃ (12 mg, 0.18 mmol)and ZnCl₂ (0.074 mL, 1 M) at RT. The reaction was stirred at 110° C. for12 h under nitrogen. The mixture was quenched with H₂O (10 mL) andextracted with EtOAc (20 mL×3). The combined organic layers were washedwith brine, dried over Na₂SO₄, concentrated in vacuo to give the crude,which was purified with Prep-TLC (DMC/MeOH=10/1) to give theN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(2-methyl-2-(2H-tetrazol-5-yl)propyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide(5 mg, yield: 23%) as a white solid. ESI-MS [M+H]⁺: 589.2. Purity: 98.2(214 nm), 96.4 (254 nm). ¹H NMR (400 MHz, CDCl₃) δ 8.70 (t, J=5.5 Hz,1H), 8.50 (s, 1H), 8.44 (d, J=2.4 Hz, 1H), 8.24-8.14 (m, 3H), 7.72 (s,1H), 6.78-6.73 (m, 1H), 5.99 (s, 1H), 5.68 (s, 2H), 4.69 (d, J=5.5 Hz,2H), 3.23 (s, 2H), 1.76-1.70 (m, 1H), 1.33 (s, 6H), 0.85-0.77 (m, 2H),0.43-0.37 (m, 2H).

Example 239

Synthesis of 5-cyclopropyl-4-fluoropyridin-2-amine

A solution of 5-bromo-4-fluoropyridin-2-amine (300 mg, 1.57 mmol) intoluene/H₂O (3 mL/0.3 mL) was added cyclopropylboronic acid (203 mg,2.36 mmol), Pd(OAc)₂ (35 mg, 0.157 mmol), K₃PO₄ (789 mg, 3.72 mmol) andSPhos (65 mg, 0.157 mmol) at RT. The mixture was stirred at 95° C. for 3h under N₂ atmosphere. The mixture was concentrated and the residue waspurified by flash silica gel chromatography (0˜40% EtOAc in PE) to give5-cyclopropyl-4-fluoropyridin-2-amine (180 mg, yield: 75%) as a yellowsolid. ESI-MS [M+H]⁺: 153.0

Synthesis of2-(chloromethyl)-6-cyclopropyl-7-fluoroimidazo[1,2-a]pyridine

To a solution of 5-cyclopropyl-4-fluoropyridin-2-amine (180 mg, 1.18mmol) in DMF (3 mL) was added 1,3-dichloropropan-2-one (601 mg, 4.72mmol) at RT. The mixture was heated to 95° C. and stirred for 16 h.Water (20 mL) was added and exacted with EtOAc (50 mL×3). The combinedorganic layers were concentrated and purified by flash silica gelchromatography (0˜50% EtOAc in PE) to give2-(chloromethyl)-6-cyclopropyl-7-fluoroimidazo[1,2-a]pyridine (100 mg,yield: 37%) as a red oil. ESI-MS [M+H]⁺: 225.0.

Synthesis of2-(azidomethyl)-6-cyclopropyl-7-fluoroimidazo[1,2-a]pyridine

To a solution of2-(chloromethyl)-6-cyclopropyl-7-fluoroimidazo[1,2-a]pyridine (100 mg,0.45 mmol) in DMF (5 mL) was added NaN₃ (29 mg, 0.45 mmol) at RT. Themixture was stirred at RT for 2 h. Water (20 mL) was added and exactedby EtOAc (50 mL×3). The combined organic layers were concentrated togive 2-(azidomethyl)-6-cyclopropyl-7-fluoroimidazo[1,2-a]pyridine (80mg, crude) as a red oil which was used into next step withoutpurification. ESI-MS [M+H]⁺: 232.0.

Synthesis of tert-butyl1-((6-cyclopropyl-7-fluoroimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate

To a solution of2-(azidomethyl)-6-cyclopropyl-7-fluoroimidazo[1,2-a]pyridine (80 mg,crude from last step) in t-BuOH/H₂O (2 mL/2 mL) was added t-butylpropiolate (51.7 mg, 0.41 mmol), sodium ascorbate (13.7 mg, 0.07 mmol)and CuSO₄ (11.0 mg, 0.07 mmol) at RT. The mixture was stirred for 2 h.Water (15 mL) was added and exacted by DCM (30 mL×3). The combinedorganic layers were concentrated to give tert-butyl1-((6-cyclopropyl-7-fluoroimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(70 mg, crude) as a red oil. ESI-MS [M+H]⁺: 358.2.

Synthesis of1-((6-cyclopropyl-7-fluoroimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicAcid

To a solution of tert-butyl1-((6-cyclopropyl-7-fluoroimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(70 mg, crude) in DCM (3 mL) was added TFA (1 mL) at RT. The mixture wasstirred for 1 h. The mixture was filtered and concentrated to give1-((6-cyclopropyl-7-fluoroimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (80 mg, crude) as a brown oil. ESI-MS [M+H]⁺: 302.1.

Synthesis ofN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-7-fluoroimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(I-239)

To a solution of1-((6-cyclopropyl-7-fluoroimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (80 mg, rrude) in DMF (2 mL) was added EDCI (76.4 mg, 0.40 mmol),HOBT (54 mg, 0.40 mmol), DIPEA (137 mg, 1.06 mmol) and(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride(62 mg, 0.26 mmol) at RT. The mixture was stirred for 16 h. The mixturewas concentrated and the residue was purified by prep-HPLC to giveN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-7-fluoroimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(5.7 mg, yield: 8% over 4 steps) as a white solid. ESI-MS [M+H]⁺: 483.0.Purity: 98.37% (214 nm), 96.66% (254 nm). ¹H NMR (400 MHz, DMSO-d₆) δ8.70 (t, J=5.5 Hz, 1H), 8.54 (s, 1H), 8.44 (d, J=2.3 Hz, 1H), 8.39 (d,J=7.5 Hz, 1H), 8.21 (d, J=7.4 Hz, 1H), 7.80 (s, 1H), 7.35 (d, J=10.9 Hz,1H), 6.80-6.74 (m, 1H), 5.71 (s, 2H), 4.69 (d, J=5.5 Hz, 2H), 1.96-1.87(m, 1H), 0.98-0.89 (m, 2H), 0.74-0.64 (m, 2H).

Example 240

Synthesis of Ethyl 6-cyclopropylimidazo[1,2-a]pyridine-2-carboxylate

A mixture of ethyl 5-cyclopropylpyridin-2-amine (6 g, 44.8 mmol) andethyl 3-bromo-2-oxopropanoate (13.0 g, 67.2 mmol) in EtOH (100 mL) wasstirred at 90° C. for 16 h. The reaction mixture was cooled to RT anddiluted with H₂O (200 mL), extracted with EtOAc (50 mL×4). The combinedorganic layers were washed with brine, dried over Na₂SO₄ andconcentrated to give the crude product, which was purified by flashcolumn chromatography (PE/EA=1/1) to give ethyl6-cyclopropylimidazo[1,2-a]pyridine-2-carboxylate (3.5 g, yield: 34%) asa brown oil. ESI-MS [M+H]⁺: 231.2.

Synthesis of Ethyl6-cyclopropyl-3-fluoroimidazo[1,2-a]pyridine-2-carboxylate

To a solution of ethyl 6-cyclopropylimidazo[1,2-a]pyridine-2-carboxylate(3.5 g, 15.2 mmol) in CHCl₃/H₂O (45 mL/15 mL) was added DMAP (1.96 g,16.1 mmol) and select-F (11.4 g, 32.2 mmol) at 0° C. The mixture wasstirred at RT for 18 h. The reaction was quenched with H₂O (100 mL) andextracted with EtOAc (100 mL×3). The combined organic layers were washedwith brine and concentrated to give the residue, which was purified byflash column chromatography to afford ethyl6-cyclopropyl-3-fluoroimidazo[1,2-a]pyridine-2-carboxylate (1.5 g,yield: 38%) as a yellow oil. ESI-MS [M+H]⁺: 249.1

Synthesis of (6-cyclopropyl-3-fluoroimidazo[1,2-a]pyridin-2-yl)methanol

To the mixture of ethyl6-cyclopropyl-3-fluoroimidazo[1,2-a]pyridine-2-carboxylate (1.3 g, 5.2mmol) in THF (50 mL) was added DIBAL-H (15.7 mL, 15.7 mmol) at −60° C.The reaction mixture was warmed to RT and stirred for 3 h. The reactionmixture quenched with saturated aqueous NH₄Cl (50 mL), and extractedwith EtOAc (50 mL×3). The combined organic layers were washed withbrine, dried over Na₂SO₄, and concentrated to give the residue, whichwas purified by flash column chromatography (PE/EA=1/2) to afford(6-cyclopropyl-3-fluoroimidazo[1,2-a]pyridin-2-yl)methanol (0.95 g,yield: 88.7%). ESI-MS [M+H]⁺: 207.1

Synthesis of2-(azidomethyl)-6-cyclopropyl-3-fluoroimidazo[1,2-a]pyridine

To a mixture of (5-cyclopropyl-1H-indol-2-yl)methanol (0.95 g, 4.6 mmol)and DPPA (3.8 g, 13.8 mmol) in DCM (20 mL) was added DBU (2.1 g, 13.8mmol) at 0° C. The reaction mixture was degassed with N₂ and stirred atRT for 18 h. The reaction mixture quenched with H₂O (30 mL) andextracted with DCM (50 mL×3). The combined organic layers were washedwith brine, dried over Na₂SO₄, and concentrated to give the residue,which was purified by flash column chromatography (PE/EA=1/1) toafforded 2-(azidomethyl)-6-cyclopropyl-3-fluoroimidazo[1,2-a]pyridine(0.8 g, yield: 75%). ESI-MS [M+H]⁺: 232.2

Synthesis of tert-butyl1-((6-cyclopropyl-3-fluoroimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate

The mixture of 2-(azidomethyl)-5-cyclopropyl-1H-indole (1.12 g, 4.484mmol), tert-butyl propiolate (734 mg, 5.81 mmol), sodium ascorbate (192mg, 0.96 mmol) and CuSO₄ (155 mg, 1.96 mmol) in t-BuOH/H₂O (5 mL/5 mL)was stirred at RT for 3 h. The reaction was diluted with H₂O (50 mL),extracted with DCM/MeOH (10/1, 500 mL×3). The combined organic layerswere washed with brine and concentrated to give the crude, which waspurified by flash column chromatography (DCM/MeOH=20/1) to affordtert-butyl1-((6-cyclopropyl-3-fluoroimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(500 mg, yield: 30%) as a yellow solid. ESI-MS [M+H]⁺: 357.1

Synthesis of1-((6-cyclopropyl-3-fluoroimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicAcid

A mixture of tert-butyl1-((6-cyclopropyl-3-fluoroimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(400 mg, 1.12 mmol) in TFA/DCM (0.5 mL/1.5 mL) was stirred at RT for 3h. The reaction was evaporated to remove the solvent to afford1-((6-cyclopropyl-3-fluoroimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (400 mg, crude) as a black oil, which was used into next stepdirectly. ESI-MS [M+H]⁺: 301.9

Synthesis ofN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-3-fluoroimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(I-240)

The mixture of1-((6-cyclopropyl-3-fluoroimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (400 mg, crude from last step),(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride(249 mg, 1.06 mmol), HATU (509 mg, 1.33 mmol) and DIPEA (808 mg, 6.23mmol) in DMF (5 mL) was stirred at to RT for 16 h. The reaction mixturewas diluted with H₂O (80 mL) and extracted with EtOAc (100 mL×3). Thecombined organic layers were washed with brine and concentrated to givethe crude, which was purified by prep-HPLC to affordN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-3-fluoroimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(50 mg, yield: 10%) as white solid. ESI-MS [M+H]⁺: 483.0. Purity: 99.06(214 nm), 100 (254 nm). ¹H NMR (400 MHz, DMSO-d₆) δ 8.71 (s, 1H), 8.56(s, 1H), 8.47 (s, 1H), 8.20 (d, J=7.4 Hz, 1H), 8.09 (s, 1H), 7.39 (d,J=9.1 Hz, 1H), 7.03-6.96 (m, 1H), 6.76 (t, J=6.9 Hz, 1H), 5.77 (s, 2H),4.69 (s, 2H), 2.05-1.95 (m Hz, 1H), 0.99-0.89 (m, 2H), 0.78-0.70 (m,2H).

Example 241

Synthesis of tert-butyl1-((6-cyclopropyl-8-formylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate

To a solution of tert-butyl1-((6-cyclopropyl-8-(hydroxymethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(2.0 g, 5.4 mmol) in DCM (50 mL) was added MnO₂ (939.6 mg, 10.8 mmol).The mixture was stirred at RT for 48 h. The mixture was filtered, andwashed with DCM (100 mL). The filtrate was concentrated to givetert-butyl1-((6-cyclopropyl-8-formylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(1.4 g, yield: 70.7%) as a yellow solid. ESI-MS [M+H]⁺: 368.2

Synthesis of tert-butyl1-((6-cyclopropyl-8-(3-ethoxy-1-hydroxy-2,2-dimethyl-3-oxopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate

To a solution of ethyl isobutyrate (474 mg, 4.08 mmol) in dry THF (30mL) was added LDA (4.28 mL, 1 M solution in THF, 4.28 mmol) at −78° C.The reaction mixture was stirred for 30 min at −78° C. Then a solutionof tert-butyl1-((6-cyclopropyl-8-formylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(300 mg, 0.817 mmol) in THF (3 mL) was added thereto. The resultingreaction mixture was stirred for another 50 min at −78° C. The reactionwas quenched with saturated aqueous NH₄Cl (50 mL), extracted with EtOAc(40 mL×3). The combined organic layers were washed with brine, driedover Na₂SO₄, concentrated to give the c rude, which was purified byPrep-TLC (DCM/MeOH=15/1) to tert-butyl1-((6-cyclopropyl-8-(3-ethoxy-1-hydroxy-2,2-dimethyl-3-oxopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(240 mg, yield: 60.7%) as a yellow solid. ESI-MS [M+H]⁺: 484.2.

Synthesis of1-((6-cyclopropyl-8-(3-ethoxy-1-hydroxy-2,2-dimethyl-3-oxopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicAcid

To a solution of tert-butyl1-((6-cyclopropyl-8-(3-ethoxy-1-hydroxy-2,2-dimethyl-3-oxopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(240 mg, 0.49 mmol) in DCM (5 mL) was added TFA (1 mL) at RT. Themixture was stirred at RT for 3 h. The reaction was concentrated invacuo to give1-((6-cyclopropyl-8-(3-ethoxy-1-hydroxy-2,2-dimethyl-3-oxopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid, which was used into next step without further purification (225 mgcrude). ESI-MS [M+H]⁺: 428.2.

Synthesis of Ethyl3-(2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)-3-hydroxy-2,2-dimethylpropanoate(I-241a)

To a solution of1-((6-cyclopropyl-8-(1-fluoroethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (225 mg, crude from previous step),(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride(125 mg, 0.53 mmol), EDCI (151 mg, 0.79 mmol), HOBT (106.7 mg, 0.79mmol) in DMF (5 mL) was added DIPEA (340 mg, 2.63 mmol). The resultingreaction was stirred at RT for 16 h. Water (50 mL) was added, extractedwith EtOAc (20 mL×3). The combined organic layers were concentrated andpurified by Prep-TLC (DCM/MeOH=10/1) to give ethyl3-(2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)-3-hydroxy-2,2-dimethylpropanoate.(170 mg, yield: 56%) as a white solid. ESI-MS [M+H]⁺: 609.2. Purity:98.6% (214 nm), 100.0% (254 nm). ¹H NMR (400 MHz, DMSO-d₆) δ 8.68 (t,J=5.5 Hz, 1H), 8.49 (s, 1H), 8.44 (d, J=2.4 Hz, 1H), 8.26 (d, J=1.4 Hz,1H), 8.20 (d, J=7.4 Hz, 1H), 7.80 (s, 1H), 6.97 (d, J=1.5 Hz, 1H),6.78-6.74 (m, 1H), 5.73 (s, 2H), 5.62 (s, 1H), 5.51 (s, 1H), 4.69 (d,J=5.5 Hz, 3H), 3.97 (q, J=7.1 Hz, 2H), 1.98-1.91 (m, 1H), 1.13-1.07 (m,6H), 0.96-0.91 (m, 5H), 0.68-0.59 (m, 2H).

Synthesis of3-(2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)-3-hydroxy-2,2-dimethylpropanoicacid (I-241b)

To a solution of ethyl3-(2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)-3-hydroxy-2,2-dimethylpropanoate(160 mg, 0.26 mmol) in THF/H₂O (4 mL/2 mL) was added LiOH.H₂O (32 mg,0.78 mmol). The resulting mixture was stirred at RT for 2 h. Thereaction was concentrated in vacuo to give the crude, which was purifiedwith Prep-HPLC to give the3-(2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)-3-hydroxy-2,2-dimethylpropanoicacid (91 mg, 59.6%). ESI-MS [M+H]⁺: 581.2. Purity: 99.52% (214 nm), 100%(254 nm). ¹H NMR (400 MHz, DMSO-d₆) δ 12.14 (s, 1H), 8.69 (t, J=5.5 Hz,1H), 8.50 (s, 1H), 8.44 (d, J=2.4 Hz, 1H), 8.26 (d, J=1.2 Hz, 1H), 8.20(d, J=7.4 Hz, 1H), 7.79 (s, 1H), 6.97 (d, J=1.4 Hz, 1H), 6.77-6.74 (m,1H), 5.74 (s, 2H), 5.58 (s, 1H), 4.69 (d, J=5.5 Hz, 2H), 1.97-1.91 (m,1H), 1.01 (s, 2H), 0.96-0.92 (m, 2H), 0.87 (s, 2H), 0.71-0.59 (m, 2H).

Example 242

Synthesis of4-(6-cyclopropyl-2-(hydroxymethyl)imidazo[1,2-a]pyridin-8-yl)-1,4-dihydro-1,2,4-triazine-5,6-dione

To a mixture of(8-amino-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methanol (406 mg, 2mmol) in MeCN (25 mL) was added HC(OEt)₃ (1.2 g, 8 mmol). The mixturewas stirred at 80° C. for 1 h. Then AcOH (180 mg, 3 mmol) and ethyl2-hydrazinyl-2-oxoacetate (670 mg, 5 mmol) was added. The resultingreaction was stirred at 80° C. for another 16 h. The reaction mixturewas filtered and dried to give4-(6-cyclopropyl-2-(hydroxymethyl)imidazo[1,2-a]pyridin-8-yl)-1,4-dihydro-1,2,4-triazine-5,6-dione(200 mg, yield: 33%) as a yellow solid, which was used for the next stepwithout further purification. ESI-MS [M+H]⁺: 300.1.

Synthesis of4-(6-cyclopropyl-2-(hydroxymethyl)imidazo[1,2-a]pyridin-8-yl)-1-ethyl-1,4-dihydro-1,2,4-triazine-5,6-dione

To a mixture of4-(6-cyclopropyl-2-(hydroxymethyl)imidazo[1,2-a]pyridin-8-yl)-1,4-dihydro-1,2,4-triazine-5,6-dione(175 mg, 0.6 mmol) and K₂CO₃ (400 mg, 2.9 mmol) in DMF (5 mL) was addedEtI (273 mg, 1.8 mmol). The mixture was stirred at RT for 2 h. Water (30mL) was added and extracted with EtOAc (50 mL×3). The filtrate waswashed with brine, dried over Na₂SO₄, concentrated to give4-(6-cyclopropyl-2-(hydroxymethyl)imidazo[1,2-a]pyridin-8-yl)-1-ethyl-1,4-dihydro-1,2,4-triazine-5,6-dione(200 mg, crude) as a yellow oil, which was used for the next stepwithout further purification. ESI-MS [M+H]⁺: 328.1.

Synthesis of4-(2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)-1-ethyl-1,4-dihydro-1,2,4-triazine-5,6-dione

To a mixture of4-(6-cyclopropyl-2-(hydroxymethyl)imidazo[1,2-a]pyridin-8-yl)-1-ethyl-1,4-dihydro-1,2,4-triazine-5,6-dione(200 mg crude) in DCM (5 mL) was added SOCl₂ (1 mL). The reactionmixture was stirred at RT for 2 h. The reaction was concentrated to give4-(2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)-1-ethyl-1,4-dihydro-1,2,4-triazine-5,6-dione(220 mg, crude) as yellow oil, which was used into next step withoutfurther purification. ESI-MS [M+H]⁺: 346.1.

Synthesis of4-(2-(azidomethyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)-1-ethyl-1,4-dihydro-1,2,4-triazine-5,6-dione

To a mixture of4-(2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)-1-ethyl-1,4-dihydro-1,2,4-triazine-5,6-dione(220 mg, crude from previous step) in DMF (5 mL) was added NaN₃ (65 mg,1 mmol). The resulting reaction mixture was stirred at RT for 3 h. Water(25 mL) was added to the reaction, and extracted with EtOAc (30 mL×3).The combined organic layers were washed with brine and dried overNa₂SO₄, concentrated to give the crude, which was purified with Prep-TLC(DCM/MeOH=15/1) to give4-(2-(azidomethyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)-1-ethyl-1,4-dihydro-1,2,4-triazine-5,6-dione(170 mg, 80% over 3 steps) as yellow oil. ESI-MS [M+H]⁺: 353.1.

Synthesis of tert-butyl1-((6-cyclopropyl-8-(1-ethyl-5,6-dioxo-5,6-dihydro-1,2,4-triazin-4(1H)-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate

To a mixture of4-(2-(azidomethyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)-1-ethyl-1,4-dihydro-1,2,4-triazine-5,6-dione(170 mg, 0.48 mmol), CuSO₄ (32 mg, 0.2 mmol) and sodium ascorbate (40mg, 0.2 mmol) in t-BuOH/H₂O (10 mL/10 mL) was added tert-butylpropiolate (95 mg, 0.75 mmol). The reaction mixture was stirred at RTfor 2 h. Water (30 mL) was added and the mixture was extracted withEtOAc (30 mL×3). The combined organic layers were washed with brine anddried over Na₂SO₄, concentrated to give crude, which was purified withPrep-TLC (DCM/MeOH=15/1) to give tert-butyl1-((6-cyclopropyl-8-(1-ethyl-5,6-dioxo-5,6-dihydro-1,2,4-triazin-4(1H)-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(200 mg, yield: 87%) as yellow oil. ESI-MS [M+H]⁺: 479.2.

Synthesis of1-((6-cyclopropyl-8-(1-ethyl-5,6-dioxo-5,6-dihydro-1,2,4-triazin-4(1H)-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicAcid

To a mixture of tert-butyl1-((6-cyclopropyl-8-(1-ethyl-5,6-dioxo-5,6-dihydro-1,2,4-triazin-4(1H)-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(200 mg, 0.42 mmol) in DCM (10 mL) was added TFA (3 mL). The reactionsolution was stirred at RT for 3 h. The reaction was concentrated togive1-((6-cyclopropyl-8-(1-ethyl-5,6-dioxo-5,6-dihydro-1,2,4-triazin-4(1H)-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (230 mg crude) as yellow oil, which was used into next step withoutfurther purification. ESI-MS [M+H]⁺: 423.2.

Synthesis ofN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(1-ethyl-5,6-dioxo-5,6-dihydro-1,2,4-triazin-4(1H)-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(I-242)

To a mixture of1-((6-cyclopropyl-8-(1-ethyl-5,6-dioxo-5,6-dihydro-1,2,4-triazin-4(1H)-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (230 mg, crude),(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride(142 mg, 0.6 mmol) and DIPEA (325 mg, 2.5 mmol) in DMF (8 mL) was addedHOBT (135 mg, 1 mmol) and EDCI (193 mg, 1 mmol). The reaction mixturewas stirred at RT for 12 h. Water (40 mL) was added and the mixture wasextracted with EtOAc (40 mL×3). The combined organic layers were washedwith brine and dried over Na₂SO₄, concentrated to give the crude, whichwas purified by Prep-HPLC (DCM/MeOH=10/1) to giveN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(1-ethyl-5,6-dioxo-5,6-dihydro-1,2,4-triazin-4(1H)-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(150 mg, yield: 59%) as an off-white solid. ESI-MS [M+H]⁺: 604.1.Purity: 98.3% (214 nm), 98.2% (254 nm). ¹H NMR (400 MHz, DMSO-d₆) δ 8.70(t, J=5.3 Hz, 1H), 8.54-8.53 (m, 2H), 8.44 (s, 1H), 8.20 (d, J=7.4 Hz,1H), 7.98 (s, 1H), 7.94 (s, 1H), 7.32 (d, J=1.5 Hz, 1H), 6.76 (t, J=7.4Hz, 1H), 5.75 (s, 2H), 4.69 (d, J=5.4 Hz, 2H), 3.92 (q, J=7.2 Hz, 2H),2.03-1.96 (m, 1H), 1.28 (t, J=7.2 Hz, 3H), 1.05-0.91 (m, 2H), 0.74-0.59(m, 2H).

Example 243

Synthesis of 5-cyclopropylpyridin-2-amine

To a solution of 5-bromopyridin-2-amine (40 g, 232 mmol) in toluene/H₂O(500 mL/50 mL) was added cyclopropylboronic acid (29.92 g, 348 mmol),Pd(OAc)₂ (65.19 g, 23.2 mmol), SPhos (10.24 g, 23.2 mmol) and K₃P₄(147.5 g, 696 mmol). The reaction mixture was stirred at 95° C. for 16 hunder nitrogen. Then the mixture was concentrated in vacuo. Water (400mL) was added and the mixture was extracted with DCM (500 mL×2). Thecombined organic layers were concentrated to give the crude product,which was purified by silica gel chromatography (PE/EtOAc=1/1) to givethe 5-cyclopropylpyridin-2-amine as a yellow solid (26 g, yield: 84%).ESI-MS [M+H]⁺: 135.1.

Synthesis of Ethyl 6-cyclopropylimidazo[1,2-a]pyridine-2-carboxylate

To a solution 5-cyclopropyl-4-methylpyridin-2-amine (5 g, 37.31 mmol) inDME (50 mL) was added ethyl 3-bromo-2-oxopropanoate (7.27 g, 37.26 mmol)at RT. The resulting mixture was stirred at 90° C. for 16 h and thenconcentrated in vacuo. H₂O (500 mL) was added, the pH value of themixture was adjusted to 8 by adding saturated NaHCO₃ solution, and thenthe mixture was extracted with EtOAc (400 mL×3). The combined organiclayers were washed with brine, dried over Na₂SO₄, and concentrated togive the crude product, which was purified by silica gel chromatography(DCM/EA=5/1) to give ethyl6-cyclopropylimidazo[1,2-a]pyridine-2-carboxylate (3.8 g, yield: 44%) asa solid. ESI-MS [M+H]⁺: 230.9.

Synthesis of 6-cyclopropylimidazo[1,2-a]pyridine-2-carbaldehyde

A solution of ethyl 6-cyclopropylimidazo[1,2-a]pyridine-2-carboxylate(3.8 g, 16.5 mmol) in DCM (60 mL) was added DIBAL-H by dropwise (16.5mL, 1 M in DCM, 16.5 mmol) was stirred at −78° C. for 5 h. The mixturewas quenched with NaHCO₃ (20 mL) and extracted with DCM (100 mL×3). Thecombined organic layers were concentrated under and purified by silicagel chromatography (EA/PE=10/1) to give6-cyclopropylimidazo[1,2-a]pyridine-2-carbaldehyde (1.65 g, yield: 54%)as a white solid. ESI-MS [M+H]⁺: 187.0

Synthesis of2-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)-2-hydroxyacetonitrile

To a solution of Na₂S₂O₅ (1.68 g, 8.86 mmol) in H₂O (150 mL) was added6-cyclopropylimidazo[1,2-a]pyridine-2-carbaldehyde (1.65 g, 8.86 mmol).After the mixture was stirred for 2 h at RT, NaCN (869 mg, 17.72 mmol)was added and the mixture was stirred for another 15 h. The precipitatewas collected and washed with H₂O (50 mL), and dried to give2-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)-2-hydroxyacetonitrile (1.62g, yield: 85%) as a white solid. ESI-MS [M+H]⁺: 214.0.

Synthesis of Methyl2-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)-2-hydroxyacetate

A solution of2-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)-2-hydroxyacetonitrile (1.3g, 6.1 mmol) in MeOH.HCl (100 mL) was stirred at 0° C. for 5 h. Themixture was treated with ice H₂O slowly at 0° C., stirred at RT for 2 h,adjusted pH>7 with sodium bicarbonate, then extracted with DCM (100mL×3), washed with brine, dried over sodium sulfate, and concentrated togive crude mixture. The crude was dissolved in MeOH (50 mL) and H₂SO₄ (2M, 5 mL) was added and the resulting mixture was refluxed for 5 h. Themixture was concentrated to give methyl2-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)-2-hydroxyacetate (1.5 g,yield: 99%) as a white solid. ESI-MS [M+H]⁺: 246.9.

Synthesis of Methyl2-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)-2-oxoacetate

A solution of methyl2-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)-2-hydroxyacetate (1.5 g,6.09 mmol) in DCM (60 mL) was added Dess-Martin (3.10 g, 7.31 mmol),then the mixture was stirred at RT for 5 h. The mixture was treated withaqueous NaHCO₃ and extracted with DCM. The combined organic layers wereconcentrated to obtain the product, which was purification by silica gelchromatography (PE/EA=1:1) to give methyl2-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)-2-oxoacetate (1.0 g, yield:67%) as a white solid. ESI-MS [M+H]⁺: 244.9.

Synthesis of Methyl2-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)-2,2-difluoroacetate

To a solution of methyl2-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)-2-oxoacetate (700 mg, 2.87mmol) in DCM (30 mL) was added DAST (2.31 g, 14.33 mmol) at 0° C., thenthe mixture was stirred at RT overnight. Water (30 mL) was added thenextracted with DCM (50 mL×3), the combined organic layers wereconcentrated to give methyl2-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)-2,2-difluoroacetate (950 mgcrude) which was used into next step without further purification.ESI-MS [M+H]⁺: 266.8.

Synthesis of2-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)-2,2-difluoroacetohydrazide

To a solution of methyl2-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)-2,2-difluoroacetate (950 mgcrude, from last step) in MeOH (20 mL) was added hydrazine hydrate (357mg, 7.14 mmol), then the mixture was stirred at RT overnight. Thesolvent was removed to give2-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)-2,2-difluoroacetohydrazide(1 g, crude) which was used in next step without further purification.ESI-MS [M+H]⁺: 267.0.

Synthesis of Methyl2-(2-(2-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)-2,2-difluoroacetyl)hydrazinyl)-2-oxoacetate

To a solution of2-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)-2,2-difluoroacetohydrazide(275 mg, crude from last step) in CH₃CN (12 mL) was added methyl2-chloro-2-oxoacetate (133 mg, 1.86 mmol), then the mixture was stirredat 0° C. for 0.5 h. The mixture was treated with H₂O (20 mL) andextracted with EtOAc (50 mL×3). The combined organic layers wereconcentrated to give the crude product which was purification by silicagel chromatography (PE/EA=1:1) to give methyl2-(2-(2-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)-2,2-difluoroacetyl)hydrazinyl)-2-oxoacetate(297 mg) as a yellow solid. ESI-MS [M+H]⁺: 352.9.

Synthesis of Methyl5-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)difluoromethyl)-1,3,4-oxadiazole-2-carboxylate

A 50 mL 3-neck flask equipped with a stir-bar and a nitrogen inlet wascharged with triphenylphosphine (313 mg, 1.19 mmol) and anhydrous DCM(17 mL) and the temperature was maintained with an ambient-temperature.Iodine (303 mg, 1.19 mmol) was added in portions over 10 minutes,allowing the iodine to dissolve before continuing the addition. Theresulting dark red solution was stirred for further 15 min. A separate50 mL 3-neck flask equipped with a stir bar, nitrogen inlet was placedin an ambient-temperature and charged with methyl2-(2-(2-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)-2,2-difluoroacetyl)hydrazinyl)-2-oxoacetate(280 mg, 0.79 mmol) and anhydrous DCM (10 mL) to give a thick whitesuspension. Triethylamine (321 mg, 3.18 mmol) was added and theresulting solution was stirred for 15 minutes to give a light brownsolution. The phosphorane solution was added. The dark red solution wasstirred for another 60 min at RT. Water was added and extracted withethyl acetate. The combined organic layers were dried (NaSO4), filteredand concentrated to give a dark brown solid which was purified by silicagel chromatography (PE/EA=1:1) to give methyl5-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)difluoromethyl)-1,3,4-oxadiazole-2-carboxylate(130 mg, yield: 49%) as a yellow solid. ESI-MS [M+H]⁺: 334.7.

Synthesis ofN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-5-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)difluoromethyl)-1,3,4-oxadiazole-2-carboxamide(I-243)

To a solution of methyl5-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)difluoromethyl)-1,3,4-oxadiazole-2-carboxylate(45 mg, 0.134 mmol) in CH₃CN (3 mL) was added DIPEA (67 mg, 0.336 mmol),then the mixture was stirred at 80° C. under microwave for 1 h. Thesolvent was removed to give the crude which was purified by Prep-HPLC togiveN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-5-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)difluoromethyl)-1,3,4-oxadiazole-2-carboxamide(14.8 mg, yield: 22%) as a white solid ESI-MS [M+H]⁺: 501.4. Purity:97.42% (214 nm) 97.90% (254 nm). ¹H NMR (400 MHz, DMSO-d₆) δ 9.88 (t,J=4.0 Hz, 1H), 8.48 (d, J=4.0 Hz, 1H), 8.42 (d, J=8.0 Hz, 2H), 8.23 (d,J=8.0 Hz, 1H), 7.55 (d, J=8.0 Hz, 1H), 7.17 (d, J=8.0 Hz, 1H), 6.79 (t,J=8.0 Hz, 1H), 4.74 (d, J=4.0 Hz, 2H), 2.01-1.98 (m, 1H), 0.98-0.94 (m,2H), 0.74-0.71 (m, 2H).

Example 244

Synthesis of2-(2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-5-cyclopropyl-1H-indol-1-yl)aceticacid (I-244)

A mixture of methyl2-(2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-5-cyclopropyl-1H-indol-1-yl)acetate(40 mg, 0.075 mmol) and LiOH.H₂O (16 mg, 0.37 mmol) in THF/H₂O (5 mL/2mL) was stirred at RT for 3 h. LCMS confirmed the starting materialconsumed completely and target material was detected. The reactionmixture was adjusted to pH-3. Then Water was added and extracted withDCM/MeOH (30 mL×5). The combined organic layers were washed with brineand concentrated. The crude product was purified by prep-HPLC toafforded2-(2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-5-cyclopropyl-1H-indol-1-yl)aceticacid (1.2 mg, yield: 3%) as a brown solid. ESI-MS [M+H]⁺: 522.1. Purity:96.69% (214 nm), 82.74% (254 nm). ¹H NMR (400 MHz, DMSO-d₆) δ 12.89 (s,1H), 8.67 (s, 1H), 8.50-8.41 (m, 2H), 8.20 (d, J=7.3 Hz, 1H), 7.28-7.19(m, 2H), 6.89 (d, J=8.5 Hz, 1H), 6.76 (t, J=6.8 Hz, 1H), 6.48 (s, 1H),5.84 (s, 2H), 5.04 (s, 2H), 4.68 (d, J=5.0 Hz, 2H), 1.96 (s, 1H), 0.89(d, J=7.2 Hz, 2H), 0.62 (d, J=4.2 Hz, 2H).

Example 245

Synthesis of tert-butyl1-((6-cyclopropyl-8-(3-ethoxy-2-methyl-3-oxoprop-1-en-1-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate

To a suspension of tert-butyl1-((6-cyclopropyl-8-formylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(450 mg, 1.23 mmol) in THF (20 mL) was added dropwise ethyl2-(triphenyl-15-phosphanylidene)propanoate (445 mg, 1.23 mmol). Theresulting reaction solution was stirred at 50° C. for 5 h. The reactionwas quenched with saturated aqueous NH₄Cl solution (20 mL). The layerswere separated and the aqueous phase was extracted with EtOAc (100mL×3). The combined organic layers were washed with saturated aqueousbrine (50 mL×2), dried over sodium sulfate and concentrated in vacuo togive the crude, which was purification by column chromatography(DCM:MeOH=50:1) to afforded the tert-butyl1-((6-cyclopropyl-8-(3-ethoxy-2-methyl-3-oxoprop-1-en-1-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(450 mg, 81%) as a yellow solid. ESI-MS [M+H]⁺: 452.3.

Synthesis of tert-butyl1-((6-cyclopropyl-8-(3-ethoxy-2-methyl-3-oxopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate

To a solution of tert-butyl1-((6-cyclopropyl-8-(3-ethoxy-2-methyl-3-oxoprop-1-en-1-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(450 mg, 1 mmol) in ethanol (20 mL) was added Pd/C (200 mg). A balloonof hydrogen gas was added and the reaction was evacuated and back-filledwith hydrogen three times. The reaction was stirred under a hydrogenballoon at 0° C. for 3 h, filtered through a pad of celite andconcentrated in vacuo to crude compound. The crude compound was purifiedby flash silica gel chromatography (EA/PE=1:2) to give the tert-butyl1-((6-cyclopropyl-8-(3-ethoxy-2-methyl-3-oxopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(300 mg, 66%) as a yellow solid. ESI-MS [M+H]⁺: 454.2.

Synthesis of1-((6-cyclopropyl-8-(3-ethoxy-2-methyl-3-oxopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicAcid

To a solution of tert-butyl1-((6-cyclopropyl-8-(3-ethoxy-2-methyl-3-oxopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(288 mg, 0.64 mmol) in DCM (10 mL) was added TFA (2 mL). The reactionmixture was stirred at 50° C. for 3 h. LCMS showed the reaction wascomplete. The solvent of the reaction mixture was evaporated underreduced pressure to give1-((6-cyclopropyl-8-(3-ethoxy-2-methyl-3-oxopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid. The crude product was used in next step without furtherpurification (300 mg, crude) as a yellow solid. ESI-MS [M+H]⁺: 398.2.

Synthesis of Ethyl3-(2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)-2-methylpropanoate(I-245a)

To a solution of1-((6-cyclopropyl-8-(3-ethoxy-2-methyl-3-oxopropyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (150 mg, crude) in dry DMF (5 mL), was added(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride(141 mg, 0.60 mmol), HATU (274 mg, 0.72 mmol) and DIPEA (387 mg, 3mmol), the reaction mixture was stirred at RT for 2 h. The reaction wasquenched with H₂O (20 mL), extracted with ethyl acetate (50 mL×3). Thecombined organic layers were washed with brine (20 mL×2), dried overanhydrous sodium sulfate and concentrated in vacuo. The residue waspurified by Prep-TLC (DCM/MeOH=10:1) to afford ethyl3-(2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)-2-methylpropanoate(100 mg, yield: 54% over 2 steps) as a white solids. ESI-MS [M+H]⁺:579.2. Purity: 97.70% (214 nm), 98.50% (254 nm). ¹H NMR (400 MHz,DMSO-d6) δ 8.71 (t, J=5.4 Hz, 1H), 8.54 (s, 1H), 8.44 (d, J=2.3 Hz, 1H),8.21 (m, 2H), 7.76 (s, 1H), 6.77 (m, 2H), 5.74 (s, 2H), 4.70 (d, J=5.5Hz, 2H), 3.96 (m, 2H), 3.08 (m, 2H), 2.90 (m, 1H), 1.93-1.83 (m, 1H),1.05 (m, 6H), 0.96-0.85 (m, 2H), 0.68-0.58 (m, 2H).

Synthesis of3-(2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)-2-methylpropanoicacid (I-245b)

To a solution of ethyl3-(2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)-2-methylpropanoate(90 mg, 0.16 mmol) was dissolved in MeOH (5 mL) and H₂O (5 mL) was addedLiOH.H₂O (54.6 mg, 1.3 mmol) at RT. The reaction mixture was stirred at50° C. for 5 h. The solvent of the reaction mixture was evaporated underreduced pressure. Then pH of the mixture was acidified by HCl (1N) toaround 2, and the precipitated solid was collected by filtration toobtain the crude product. The crude product was purified by prep-HPLC togive the3-(2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)-2-methylpropanoicacid (25 mg, yield 28%) as a white solid. ESI-MS [M+H]⁺: 551.2. Purity:99.76% (214 nm), 100% (254 nm). ¹H NMR (400 MHz, DMSO-d6) δ 12.18 (s,1H), 8.71 (t, J=5.4 Hz, 1H), 8.55 (s, 1H), 8.44 (d, J=2.3 Hz, 1H), 8.20(m, 2H), 7.75 (s, 1H), 6.77 (m, 2H), 5.74 (s, 2H), 4.70 (d, J=5.4 Hz,2H), 3.12 (m, 1H), 2.99 (m, 1H), 2.83 (m, 1H), 1.88 (m, 1H), 1.05 (d,J=6.9 Hz, 3H), 0.95-0.85 (m, 2H), 0.70-0.58 (m, 2H).

Example 246

Synthesis of Ethyl 5-cyclopropyl-1H-indole-2-carboxylate

A mixture of ethyl 5-bromo-1H-indole-2-carboxylate (15 g, 55.9 mmol),cyclopropylboronic acid (14.4 g, 167.7 mmol), Pd(OAc)₂ (1.29 g, 5.59mmol), SPhos (2.29 g, 5.59 mmol) and K₃PO₄ (35.6 g, 167.7 mmol) intoluene/H₂O (150 mL/15 mL) was stirred at 90° C. for 16 h. The reactionmixture was filtered, washed with EtOAc (300 mL). The filtrate wasconcentrated in vacuo to give the crude product, which was purified withsilica gel chromatography (EA/PE=1/3) to give ethyl5-cyclopropyl-1H-indole-2-carboxylate (7.2 g, yield: 56.7%) as a yellowsolid. ESI-MS [M+H]⁺: 230.1

Synthesis of (5-cyclopropyl-1H-indol-2-yl)methanol

To the solution of 2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine(9.0 g, 39.3 mmol) in THF (100 mL) was added LAH (1.8 g, 47.2 mmol) at0° C. portionwise. The mixture was stirred at 0° C. for 2 h. Thereaction was quenched with H₂O (2 mL), 10% NaOH solution (2 mL) and thenH₂O (6 mL) at 0° C. The mixture was filtered and the cake was washedwith EtOAc (100 mL). The filtrate was concentrate to give the crude,which was purified by flash column chromatography (PE/EA=1/2) toafforded (5-cyclopropyl-1H-indol-2-yl)methanol (7.0 g, yield: 95%) asyellow oil. ESI-MS [M+H]⁺: 188.0

Synthesis of 2-(azidomethyl)-5-cyclopropyl-1H-indole

To the mixture of (5-cyclopropyl-1H-indol-2-yl)methanol (5.61 g, 30.0mmol) and DPPA (2.48 g, 90.0 mmol) in DCM (100 mL) was added DBU (13.7g, 90 mmol) at 0° C. The reaction mixture was degassed with N₂ andstirred at RT for 18 h. The reaction mixture was quenched with H₂O (200mL) and extracted with DCM (100 mL×3). The combined organic layers werewashed with brine, dried over Na₂SO₄, concentrated to give the crude,which was purified by flash column chromatography (PE/EA=1/1) toafforded 2-(azidomethyl)-5-cyclopropyl-1H-indole (2.5 g, yield: 39%).ESI-MS [M+H]⁺: 213.0

Synthesis of tert-butyl1-((5-cyclopropyl-1H-indol-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate

A mixture of 2-(azidomethyl)-5-cyclopropyl-1H-indole (4.9 g, 23.11mmol), tert-butyl propiolate (3.49 g, 27.73 mmol), sodium ascorbate (915mg, 4.62 mmol) and CuSO₄ (735 mg, 4.62 mmol) in t-BuOH/H₂O (25 mL/25 mL)was stirred at RT for 3 h. The reaction was diluted with H₂O (100 mL),extracted with DCM/MeOH (10/1, 100 mL×3). The combined organic layerswere washed with brine and dried over Na₂SO₄, concentrated to give thecrude, which was purified by flash column chromatography (DCM/MeOH=20/1)to afforded tert-butyl1-((5-cyclopropyl-1H-indol-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(3 g, yield: 38%) as a solid. ESI-MS [M+H]⁺: 339.1

Synthesis of tert-butyl1-((5-cyclopropyl-1-(2-methoxy-2-oxoethyl)-1H-indol-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate

A mixture of tert-butyl1-((5-cyclopropyl-1H-indol-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(400 mg, 1.18 mmol), methyl 2-chloroacetate (256 mg, 2.37 mmol), andCs₂CO₃ (770 mg, 2.37 mmol) in DMF (4 mL) was stirred at RT for 18 h. Thereaction mixture was diluted with H₂O (50 mL), extracted with EtOAc (50mL×3). The combined organic layers were washed with brine, dried overNa₂SO₄, and concentrated. The residue was purified by flash columnchromatography (DCM/MeOH=25/1) to afforded ethyl2-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)oxazole-4-carboxylate(450 mg, yield: 93%) as a yellow solid. ESI-MS [M+H]⁺: 411.2

Synthesis of1-((5-cyclopropyl-1-(2-methoxy-2-oxoethyl)-1H-indol-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicAcid

To the mixture of ethyl2-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)oxazole-4-carboxylate(450 mg, 1.1 mmol) and NaI (495 mg, 3.3 mmol) in MeCN (10 mL) was addedTMSCl (356 mg, 3.3 mmol) at RT. And the reaction was stirred at RT for 3h. Water (5 mL) was added to the reaction, and the mixture wasfreeze-dried to afforded1-((5-cyclopropyl-1-(2-methoxy-2-oxoethyl)-1H-indol-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (900 mg, crude) as a yellow-red solid which was used in next stepdirectly. ESI-MS [M+H]⁺: 354.9

Synthesis of Methyl2-(2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-5-cyclopropyl-1H-indol-1-yl)acetate(I-246)

A mixture of1-((5-cyclopropyl-1-(2-methoxy-2-oxoethyl)-1H-indol-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (900 mg, crude),(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride(389 mg, 1.65 mmol), HOBT (223 mg, 1.65 mmol), EDCI (315 mg, 1.65 mmol)and DIPEA (426 mg, 3.3 mmol) in DMF (5 mL) was stirred at to RT for 3 h.The reaction mixture was diluted with H₂O (80 mL) and extracted withEtOAc (100 mL×3). The combined organic layers were washed with brine,dried over Na₂SO₄, and concentrated. The residue was purified byprep-HPLC to afforded methyl2-(2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-5-cyclopropyl-1H-indol-1-yl)acetate(40 mg, yield: 7%) as a white solid. ESI-MS [M+H]⁺: 536.1. Purity:99.72% (214 nm), 97.06% (254 nm). ¹H NMR (400 MHz, DMSO-d₆) δ 8.70 (t,J=5.4 Hz, 1H), 8.46 (s, 1H), 8.43 (d, J=2.4 Hz, 1H), 8.20 (d, J=7.4 Hz,1H), 7.28-7.22 (m, 2H), 6.93-6.86 (m, 1H), 6.80-6.72 (m, 1H), 6.54 (s,1H), 5.86 (s, 2H), 5.18 (s, 2H), 4.68 (d, J=5.5 Hz, 2H), 3.49 (s, 3H),2.01-1.90 (m, 1H), 0.93-0.86 (m, 2H), 0.66-0.59 (m, 2H).

Example 247

Synthesis of benzyl1-((8-((tert-butoxycarbonyl)amino)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate

To a mixture of benzyl1-((8-bromo-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(1.2 g, 2.65 mmol), NH₂Boc (372 mg, 3.2 mol) and Cs₂CO₃ (2.16 g, 6.63mmol) in dioxane (20 mL) was added Pd₂(dba)₃ (280 mg, 0.27 mmol) andXantPhos (156 mg, 0.27 mmol). The reaction mixture was stirred at 100°C. for 16 h. Water (50 mL) was added to the reaction, extracted withEtOAc (50 mL×3). The combined organic layers were washed with brine,dried over Na₂SO₄, filtrated and concentrated to get the residue, whichwas purified by silica gel chromatography (PE/EA=3/1 to 1/1) to givebenzyl1-((8-((tert-butoxycarbonyl)amino)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(800 mg, yield: 62%) as a yellow oil. ESI-MS [M+H]⁺: 489.2

Synthesis of1-((8-((tert-butoxycarbonyl)amino)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicAcid

A mixture of benzyl1-((8-((tert-butoxycarbonyl)amino)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(800 mg, 1.64 mmol) and Pd/C (100 mg, 10%) in EtOH (30 mL) was stirredat RT for 5 h under H₂ atmosphere. The reaction mixture was filtrated,the cake was washed with MeOH (50 mL). The filtrate was concentrated togive1-((8-((tert-butoxycarbonyl)amino)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (650 mg, yield: 100%) as a yellow solid, which was used into nextstep without further purification. ESI-MS [M+H]⁺: 399.1.

Synthesis of tert-butyl(2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)carbamate

To the mixture of1-((8-((tert-butoxycarbonyl)amino)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (650 mg, 1.63 mmol),(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride(460 mg, 1.95 mmol) and DIPEA (1.1 g, 8.15 mmol) in DMF (10 mL) wasadded HOBT (440 mg, 3.26 mmol) and EDC (626 mg, 3.26 mmol). The mixturewas stirred at RT for 16 h. Water (50 mL) was added to the reaction,extracted with EtOAc (50 mL×3). The combined organic layers were washedwith brine, dried over Na₂SO₄, filtrated and concentrated. The residuewas purified by silica gel chromatography (DCM/MeOH=10/1) to givetert-butyl(2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)carbamate(850 mg, yield: 90%) as a yellow solid. ESI-MS [M+H]⁺: 581.1.

Synthesis of1-((8-amino-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-1,2,3-triazole-4-carboxamide

A mixture of tert-butyl(2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)carbamate(850 mg, 1.46 mmol) in 10 mL of HCl (4N solution in dioxane) was stirredat RT for 3 h. The reaction was concentrated to give1-((8-amino-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(700 mg, crude) as a yellow solid. ESI-MS [M+H]⁺: 480.1.

Synthesis ofN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(5,6-dioxo-5,6-dihydro-1,2,4-triazin-4(1H)-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide

To a mixture of1-((8-amino-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(350 mg, 0.73 mmol) and TEA (147 mg, 1.46 mmol) in McCN (15 mL) wasadded HC(OEt)₃ (432 mg, 2.92 mmol). The reaction mixture was stirred at80° C. for 1 h. Then AcOH (66 mg, 1.1 mmol) and ethyl2-hydrazinyl-2-oxoacetate (241 mg, 1.82 mmol) was added thereto. Afterstirred at 80° C. for 16 h, the reaction was concentrated to give thecrude, which was purified by Prep-TLC (DCM/MeOH=10/1) to giveN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(5,6-dioxo-5,6-dihydro-1,2,4-triazin-4(1H)-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(20 mg, yield: 4.5%) as a white solid. ESI-MS [M+H]⁺: 576.1. Purity:98.2% (214 nm), 98.0% (254 nm). ¹H NMR (400 MHz, DMSO-d₆) δ 12.53 (s,1H), 8.71 (t, J=5.3 Hz, 1H), 8.54-8.53 (m, 2H), 8.44 (d, J=2.1 Hz, 1H),8.20 (d, J=7.4 Hz, 1H), 7.92 (s, 1H), 7.87 (s, 1H), 7.32 (s, 1H),6.80-6.72 (m, 1H), 5.74 (s, 2H), 4.69 (d, J=5.4 Hz, 2H), 2.03-1.95 (m,1H), 1.00-0.96 (m, 2H), 0.71-0.67 (m, 2H).

Example 248

Synthesis of Ethyl4-(2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)-4H-1,2,4-triazole-3-carboxylate(I-248)

To a mixture of1-((8-amino-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(350 mg, 0.73 mmol) and TEA (147 mg, 1.46 mmol) in McCN (15 mL) wasadded HC(OEt)₃ (432 mg, 2.92 mmol). The mixture was stirred at 80° C.for 1 h. Then AcOH (66 mg, 1.1 mmol) and ethyl 2-hydrazinyl-2-oxoacetate(241 mg, 1.82 mmol) was added. After stirred at 80° C. for 16 h, cooled,concentrated and purified by Prep-TLC (DCM/MeOH=10/1) to ethyl4-(2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)-4H-1,2,4-triazole-3-carboxylate(10 mg, yield: 2.3%) as a white solid. ESI-MS [M+H]⁺: 604.1. Purity:96.6% (214 nm), 94.4% (254 nm). ¹H NMR (400 MHz, DMSO-d₆) δ 9.07 (s,1H), 8.69 (t, J=5.5 Hz, 1H), 8.55 (d, J=1.3 Hz, 1H), 8.51-8.37 (m, 2H),8.20 (d, J=7.4 Hz, 1H), 7.97 (s, 1H), 7.43 (d, J=1.5 Hz, 1H), 6.76 (dd,J=7.3, 6.6 Hz, 1H), 5.69 (s, 2H), 4.69 (d, J=5.5 Hz, 2H), 3.97 (q, J=7.1Hz, 2H), 2.03-1.97 (m, 1H), 1.06-0.94 (m, 2H), 0.87 (t, J=7.1 Hz, 3H),0.81-0.68 (m, 2H).

Example 249

Synthesis ofN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(3-methyl-4H-1,2,4-triazol-4-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(I-249)

To a mixture of1-((8-amino-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(48 mg, 0.1 mmol) and TEA (20 mg, 0.2 mmol) in MeCN (3 mL) was addedHC(OEt)3 (60 mg, 0.4 mmol). The mixture was stirred at 80° C. for 1 h.Then AcOH (18 mg, 0.3 mmol) and acetohydrazide (19 mg, 0.25 mmol) wasadded to the reaction above. After stirred at 80° C. for 16 h, Thereaction was concentrated to give the crude, which was purified byPrep-TLC (DCM/MeOH=10/1) toN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(3-methyl-4H-1,2,4-triazol-4-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(20 mg, yield: 37%) as a yellow solid. ESI-MS [M+H]⁺: 546.1. Purity:97.0% (214 nm), 98.3% (254 nm). ¹H NMR (400 MHz, DMSO-d₆) δ 8.77-8.65(m, 2H), 8.54 (s, 2H), 8.44 (d, J=2.4 Hz, 1H), 8.21 (d, J=7.4 Hz, 1H),7.98 (s, 1H), 7.30 (d, J=1.4 Hz, 1H), 6.82-6.72 (m, 1H), 5.74 (s, 2H),4.69 (d, J=5.5 Hz, 2H), 2.26 (s, 3H), 2.03-1.96 (m, 1H), 1.00-0.92 (m,2H), 0.81-0.71 (m, 2H).

Example 250

Synthesis of tert-butyl1-((6-cyclopropyl-8-(2-oxa-6-azaspiro[3.3]heptan-6-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate

A mixture of tert-butyl1-((8-bromo-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(350 mg, 0.837 mmol), 2-oxa-6-azaspiro[3.3]heptane (124 mg, 1.255 mmol),Pd₂(dba)₃ (77 mg, 0.0837 mmol), XantPhos (97 mg, 0.167 mmol) and K₂CO₃(347 mg, 2.51 mmol) in dioxane (8 mL) was stirred at 100° C. for 16 hunder N₂. The reaction mixture was concentrated and diluted in DCM (80mL), washed with H₂O (80 mL) and brine (80 mL), dried over Na₂SO₄,concentrated to give the crude, which was purified by silica gelchromatography (EA/PE=1/2) to give tert-butyl1-((6-cyclopropyl-8-(2-oxa-6-azaspiro[3.3]heptan-6-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(290 mg, yield: 79%) as a light brown solid. ESI-MS [M+H]⁺: 437.2.

Synthesis of1-((6-cyclopropyl-8-(2-oxa-6-azaspiro[3.3]heptan-6-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicAcid

To a solution of tert-butyl1-((6-cyclopropyl-8-(2-oxa-6-azaspiro[3.3]heptan-6-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(120 mg, 0.275 mmol) in methanol (3 mL), THF (3 mL) and H₂O (1 mL) wasadded lithium hydroxide monohydrate (46 mg, 1.1 mmol). The mixture wasstirred at 40° C. for 5 h. The reaction was concentrated to remove MeOHand THF. And the residue was diluted in H₂O (20 mL), then the pH wasacidified to 5-6 by HCl (0.5 M) and extracted with DCM (30 mL×5). Thecombined organic layers were dried over Na₂SO₄, concentrated and driedin vacuo to give1-((6-cyclopropyl-8-(2-oxa-6-azaspiro[3.3]heptan-6-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (80 mg, 76%) as a white solid. ESI-MS [M+H]⁺: 381.1.

Synthesis ofN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(2-oxa-6-azaspiro[3.3]heptan-6-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(I-250)

A mixture of1-((6-cyclopropyl-8-(2-oxa-6-azaspiro[3.3]heptan-6-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (80 mg, 0.21 mmol),(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride(59 mg, 0.25 mmol), EDCI (81 mg, 0.42 mmol), HOBT (57 mg, 0.42 mmol) andDIPEA (163 mg, 1.26 mmol) in DMF (5 mL) was stirred at 25° C. for 16 h.The reaction mixture was poured into H₂O (50 mL) and extracted withEtOAc/THF (50 mL×2, 5/1). The combined organics were washed with brine(100 mL), dried over Na₂SO₄, concentrated and purified by prep-TLC(DCM/MeOH=15/1) to giveN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(2-oxa-6-azaspiro[3.3]heptan-6-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(70 mg, yield: 59%) as a white solid. ESI-MS [M+H]⁺: 562.1. Purity:98.96% (214 nm), 98.79% (254 nm). ¹H NMR (400 MHz, DMSO-d₆) δ 8.71 (t,J=5.3 Hz, 1H), 8.50 (s, 1H), 8.44 (d, J=2.2 Hz, 1H), 8.20 (d, J=7.4 Hz,1H), 7.72-7.68 (m, 2H), 6.76 (t, J=6.9 Hz, 1H), 5.70-5.67 (m, 3H),4.73-4.68 (m, 6H), 4.24 (s, 4H), 1.86-1.78 (m, 1H), 0.88-0.82 (m, 2H),0.67-0.56 (m, 2H).

Example 251

Synthesis of tert-butyl1-((5-cyclopropyl-1-(3-ethoxy-3-oxopropyl)-1H-indol-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate

The mixture of tert-butyl1-((5-cyclopropyl-1H-indol-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(500 mg, 1.48 mmol), ethyl 3-iodopropanoate (508 mg, 2.23 mmol) andCs₂CO₃ (1.45 mg, 4.44 mmol) in DMF (10 mL) was stirred at RT for 3 h.The reaction mixture was diluted with H₂O (100 mL) and extracted withEtOAc (30 mL×3). The combined organic layers were washed with saturatedbrine and concentrated. The residue was purified by flash columnchromatography to afforded tert-butyl1-((5-cyclopropyl-1-(3-ethoxy-3-oxopropyl)-1H-indol-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(550 mg, yield: 85%) as a yellow oil. ESI-MS [M+H]⁺: 439.1

Synthesis of1-((5-cyclopropyl-1-(3-ethoxy-3-oxopropyl)-1H-indol-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicAcid

To the mixture of tert-butyl1-((5-cyclopropyl-1-(3-ethoxy-3-oxopropyl)-1H-indol-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(500 mg, 1.14 mmol) and NaI (342 mg, 2.28 mmol) in MeCN (50 mL) wasadded TMSCl (370 mg, 3.38 mmol) at RT and it was stirred at RT for 3 h.The reaction was evaporated to remove the solvent to afford1-((5-cyclopropyl-1-(3-ethoxy-3-oxopropyl)-1H-indol-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (800 mg, crude) as a light red oil which was used in next stepdirectly. ESI-MS [M+H]⁺: 383.2

Synthesis of Ethyl3-(2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-5-cyclopropyl-1H-indol-1-yl)propanoate

The mixture of1-((5-cyclopropyl-1-(2-methoxy-2-oxoethyl)-1H-indol-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (800 mg, 1.14 mmol, crude),(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride(404 mg, 1.71 mmol), HOBT (231 mg, 1.71 mmol), EDCI (327 mg, 1.71 mmol)and DIPEA (441 mg, 3.42 mmol) in DMF (5 mL) was stirred at to RT for 3h. The reaction mixture was diluted with H₂O (80 mL) and extracted withEtOAc (30 mL×3). The combined organic layers were washed with saturatedsalt H₂O and concentrated. The residue was purified by prep-HPLC toafford ethyl3-(2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-5-cyclopropyl-1H-indol-1-yl)propanoate(110 mg, yield: 18%) as a white solid. ESI-MS [M+H]⁺: 564.2. Purity:99.21% (214 nm), 98.16% (254 nm). ¹H NMR (400 MHz, DMSO-d₆) δ 8.72 (t,J=5.4 Hz, 1H), 8.54 (s, 1H), 8.44 (d, J=2.4 Hz, 1H), 8.20 (d, J=7.4 Hz,1H), 7.34 (d, J=8.5 Hz, 1H), 7.23 (d, J=1.3 Hz, 1H), 6.94-6.87 (m, 1H),6.80-6.70 (m, 1H), 6.39 (s, 1H), 5.93 (s, 2H), 4.69 (d, J=5.5 Hz, 2H),4.43 (t, J=7.1 Hz, 2H), 4.00 (q, J=7.1 Hz, 2H), 2.58 (t, J=7.1 Hz, 2H),2.00-1.90 (m, 1H), 1.10 (t, J=7.1 Hz, 3H), 0.94-0.84 (m, 2H), 0.66-0.57(m, 2H).

Synthesis of3-(2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-5-cyclopropyl-1H-indol-1-yl)propanoicacid (I-251)

The mixture of methyl2-(2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-5-cyclopropyl-1H-indol-1-yl)acetate(80 mg, 0.142 mmol) and LiOH.H₂O (30 mg, 0.710 mmol) in THF/H₂O (5 mL/2mL) was stirred at RT for 3 h. The reaction mixture was adjusted topH-3. The mixture was filtered and the solid was washed with H₂O (5mL×3). Then the solid was freeze-drying to give3-(2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-5-cyclopropyl-1H-indol-1-yl)propanoicacid (50 mg, yield: 65.8%) as a white solid. ESI-MS [M+H]⁺: 536.2.Purity: 98.73% (214 nm), 96.40% (254 nm). ¹H NMR (400 MHz, DMSO-d₆) δ12.41 (s, 1H), 8.72 (t, J=5.4 Hz, 1H), 8.53 (s, 1H), 8.45 (d, J=2.3 Hz,1H), 8.20 (d, J=7.4 Hz, 1H), 7.34 (d, J=8.5 Hz, 1H), 7.23 (d, J=1.1 Hz,1H), 6.94-6.87 (m, 1H), 6.80-6.72 (m, 1H), 6.36 (s, 1H), 5.94 (s, 2H),4.69 (d, J=5.4 Hz, 2H), 4.40 (t, J=7.1 Hz, 2H), 2.54 (t, J=7.1 Hz, 2H),1.99-1.91 (m, 1H), 0.94-0.83 (m, 2H), 0.67-0.56 (m, 2H).

Example 252

Synthesis of 6-cyclopropylbenzo[d]thiazole

To a solution of 6-bromobenzo[d]thiazole (1 g, 4.67 mmol) in dioxane/H₂O(60 mL/6 mL) was added cyclopropylboronic acid (803 mg, 9.34 mmol),Pd(OAc)₂ (105 mg, 0.467 mmol), PCy₃ (262 mg, 0.934 mmol) and K₃PO₄(2.974 g, 14 mmol). The reaction mixture was stirred at 100° C. for 14 hunder nitrogen. Then the mixture was concentrated in vacuo. Water (40mL) was added and the mixture was extracted with EtOAc (60 mL×3). Thecombined organic layers were concentrated to give the crude product,which was purified by silica gel chromatography (PE/EtOAc=20/1) to givethe 6-cyclopropylbenzo[d]thiazole as a yellow solid (769 mg, yield:94%). ESI-MS [M+H]⁺: 176.1.

Synthesis of Ethyl 6-cyclopropylbenzo[d]thiazole-2-carboxylate

To a solution 6-cyclopropylbenzo[d]thiazole (689 mg, 3.93 mmol) in dryTHF (30 mL) at −78° C. was added LiHMDS (921 mg, 5.5 mmol) dropwise andthe mixture was stirred for 30 min at −78° C. And the ethylcarbonochloridate (640 mg, 5.9 mmol) was added dropwise over a period of5 min. The resulting mixture was stirred at −78° C. for additional 30min. Then the reaction was quenched with H₂O (30 mL), THF wasconcentrated in vacuo and extracted with EtOAc (50 mL×3). The combinedorganic layers were dried over Na₂SO₄, and concentrated to give thecrude product, which was purified by silica gel chromatography(PE/EtOAc=20/1) to give ethyl6-cyclopropylbenzo[d]thiazole-2-carboxylate (236 mg, yield: 24%) as ayellow oil. ESI-MS [M+H]⁺: 247.9.

Synthesis of (6-cyclopropylbenzo[d]thiazol-2-yl)methanol

To a solution ethyl 6-cyclopropylbenzo[d]thiazole-2-carboxylate (186 mg,0.75 mmol) in MeOH (6 mL) was added NaBH₄ (57 mg, 1.5 mmol). The mixturewas stirred for 2 h at RT. Then the reaction was quenched with H₂O (20mL), concentrated in vacuo and extracted with EtOAc (30 mL×3). Thecombined organic layers were dried over Na₂SO₄, and concentrated to givethe crude product, which was purified by silica gel chromatography(PE/EtOAc=2/1) to give ethyl (6-cyclopropylbenzo[d]thiazol-2-yl)methanol(107 mg, yield: 69%) as a yellow oil. ESI-MS [M+H]⁺: 206.0.

Synthesis of 2-(chloromethyl)-6-cyclopropylbenzo[d]thiazole

To a solution of ethyl (6-cyclopropylbenzo[d]thiazol-2-yl)methanol (107mg, 0.52 mmol) in SOCl₂ (10 mL). The reaction mixture was stirred at RTfor 2 h. Then the mixture was concentrated in vacuo to give2-(azidomethyl)-6-cyclopropylbenzo[d]thiazole (116 mg, crude) as ayellow oil. ESI-MS [M+H]⁺: 223.9.

Synthesis of 2-(azidomethyl)-6-cyclopropylbenzo[d]thiazole

To a solution of ethyl 2-(chloromethyl)-6-cyclopropylbenzo[d]thiazole(116 mg, crude from last step) and NaN₃ (34 mg, 0.52 mmol) in DMF (5mL). The reaction mixture was stirred at RT for 5 h. Water (50 mL) wasadded and extracted with EtOAc (50 mL×3). The combined organic layerswere washed with brine, dried over Na₂SO₄, filtered and concentrated togive 2-(azidomethyl)-6-cyclopropylbenzo[d]thiazole (105 mg, crude) as ayellow solid. This material was used directly in the next step withoutfurther purification. ESI-MS [M+H]⁺: 231.0.

Synthesis of Ethyl1-((6-cyclopropylbenzo[d]thiazol-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate

To a solution 2-(azidomethyl)-6-cyclopropylbenzo[d]thiazole (105 mg,crude), ethyl propiolate (89 mg, 0.91 mmol), CuSO₄ (23 mg, 0.091 mmol)and sodium ascorbate (27 mg, 0.136 mmol) in t-BuOH (3 mL) and H₂O (3mL). The mixture was stirred for 2 h at RT. Then the reaction wasconcentrated in vacuo. Water (20 mL) was added to the residue, andextracted with EtOAc (20 mL×3). The combined organic layers were driedover Na₂SO₄, and concentrated to give the crude product, which waspurified by silica gel chromatography (DCM/MeOH=30/1) to give ethyl1-((6-cyclopropylbenzo[d]thiazol-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(130 mg, yield: 76% over 3 steps) as a yellow solid. ESI-MS [M+H]⁺:329.0.

Synthesis of1-((6-cyclopropylbenzo[d]thiazol-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicAcid

A solution of ethyl1-((6-cyclopropylbenzo[d]thiazol-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(87 mg, 0.26 mmol) and LiOH.H₂O (22 mg, 0.52 mmol) in a mixed solvent ofTHF/H₂O (3 mL/3 mL) was stirred at RT overnight. Then the reaction wasconcentrated to give the residue. The pH of the residue was adjusted to5 by HCl (2N) and then concentrated in vacuo to give1-((6-cyclopropylbenzo[d]thiazol-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (100 mg, crude) as a yellow solid. This material was used directlyin the next step without further purification. ESI-MS [M+H]⁺: 300.8.

Synthesis ofN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylbenzo[d]thiazol-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(I-252)

A mixture of1-((6-cyclopropylbenzo[d]thiazol-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (100 mg, crude),(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride(71 mg, 0.30 mmol), HATU (98 mg, 0.51 mmol) and DIPEA (164 mg, 1.27mmol) in DMF (5 mL). The resulting mixture was stirred for 3 h at RT.The mixture was concentrated to remove DMF to give the crude product,which was purified by prep-HPLC to giveN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylbenzo[d]thiazol-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(17 mg, yield: 14%) as a light yellow solid. ESI-MS [M+H]⁺: 482.0.Purity: 100% (214 nm) 97.96% (254 nm). ¹H NMR (400 MHz, DMSO-d₆) δ 8.81(t, J=4.0 Hz, 1H), 8.74 (s, 1H), 8.45 (s, 1H), 8.21 (d, J=7.4 Hz, 1H),7.85 (d, J=8.5 Hz, 1H), 7.79 (s, 1H), 7.24 (d, J=8.4 Hz, 1H), 6.76 ((t,J=4.2 Hz, 1H), 6.18 (s, 2H), 4.71 (d, J=5.2 Hz, 2H), 2.01-1.98 (m, 1H),1.01-0.97 (m, 2H), 0.75-0.72 (m, 2H).

Example 253

Synthesis ofN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(3,5-dimethyl-4H-1,2,4-triazol-4-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(I-253)

To a mixture of1-((8-amino-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(100 mg, 0.2 mmol) in CH₃CN (2 mL) was added 1,1,1-trimethoxyethane (124mg, 1.0 mmol), mixture was stirred at 80° C. for 1 h. And thenacetohydrazide (81 mg, 1.1 mmol) and AcOH (72 mg, 1.2 mmol) was added tothe reaction above. The resulting reaction mixture was stirred at 80° C.for another 16 h. The reaction mixture was added saturated aqueousNaHCO₃, extracted by EtOAc (50 mL×3). The combined organic layers werewashed by brine, dried over Na₂SO₄, filtered, concentrated to give thecrude, which was purified by Prep-HPLC to obtainN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(3,5-dimethyl-4H-1,2,4-triazol-4-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(24 mg, yield: 21%) as a white solid. ESI-MS [M+H]⁺: 560.1. Purity:99.08% (214 nm), 99.27% (254 nm). ¹H NMR (400 MHz, DMSO-d₆) δ 8.70 (t,J=6.0 Hz, 1H), 8.55-8.54 (m, 2H), 8.45 (d, J=4 Hz, 1H), 8.21 (d, J=8.0Hz, 1H), 7.95 (s, 1H), 7.33 (d, J=4.0 Hz, 1H), 6.76 (t, J=6.0 Hz, 1H)5.73 (s, 2H), 4.70 (d, J=4.0 Hz, 2H), 2.11 (s, 6H), 2.03-1.96 (m, 1H),0.99-0.95 (m, 2H), 0.78-0.74 (m, 2H).

Example 254

Synthesis of tert-butyl1-((5-cyclopropyl-1-(4-(methoxycarbonyl)phenyl)-1H-indol-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate

A mixture of tert-butyl1-((5-cyclopropyl-1H-indol-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(600 mg, 1.78 mmol), methyl 4-iodobenzoate (1.86 g, 7.10 mmol),1,2-ethanediamine (32 mg, 0.36 mmol), CuI (69 g, 0.36 mmol) and K₃PO₄(755 mg, 3.56 mmol) in dioxane (10 mL) was degassed with N₂ and stirredat 100° C. for 18 h. The reaction mixture was cooled to RT and dilutedwith H₂O (50 mL) and extracted with EtOAc (50 mL×3). The combinedorganic layers were washed with saturated salt H₂O and concentrated. Theresidue was purified by flash column chromatography to affordedtert-butyl1-((5-cyclopropyl-1-(4-(methoxycarbonyl)phenyl)-1H-indol-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(430 mg yield: 51%) as a yellow solid. ESI-MS [M+H]⁺: 473.1

Synthesis of1-((5-cyclopropyl-1-(4-(methoxycarbonyl)phenyl)-1H-indol-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicAcid

To a mixture of tert-butyl1-((5-cyclopropyl-1-(4-(methoxycarbonyl)phenyl)-1H-indol-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(310 mg, 0.66 mmol) and NaI (197 mg, 1.31 mmol) in MeCN (10 mL) wasadded TMSCl (213 mg, 1.97 mmol) at RT and it was stirred at RT for 3 h.Evaporated to remove the solvent to afforded1-((5-cyclopropyl-1-(4-(methoxycarbonyl)phenyl)-1H-indol-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (600 mg, crude) as a yellow-red oil which was used into next stepdirectly. ESI-MS [M+H]⁺: 417.2

Synthesis of Methyl4-(2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-5-cyclopropyl-1H-indol-1-yl)benzoate(I-254)

The mixture of1-((5-cyclopropyl-1-(2-methoxy-2-oxoethyl)-1H-indol-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (60 mg, crude from last step),(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride(23.3 mg, 0.1 mmol), HOBT (134 mg, 0.1 mmol), EDCI (190 mg, 0.1 mmol)and DIPEA (25.4 mg, 0.2 mmol) in DMF (4 mL) was stirred at to RT for 3h. The reaction mixture was diluted with H₂O (30 mL) and extracted withEtOAc (30 mL×3). The combined organic layer was washed with brine andconcentrated. The residue was purified by prep-HPLC to afforded methyl4-(2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-5-cyclopropyl-1H-indol-1-yl)benzoate(11 mg, yield: 28%) as white solid. ESI-MS [M+H]⁺: 598.2. Purity: 98.49%(214 nm), 96.69% (254 nm). ¹H NMR (400 MHz, DMSO-d₆) δ 8.64 (t, J=5.4Hz, 1H), 8.44 (d, J=2.4 Hz, 1H), 8.26 (s, 1H), 8.20 (d, J=7.4 Hz, 1H),8.09 (d, J=8.5 Hz, 2H), 7.52 (d, J=8.5 Hz, 2H), 7.35 (s, 1H), 7.00 (d,J=8.5 Hz, 1H), 6.95-6.88 (m, 1H), 6.80-6.72 (m, 1H), 6.64 (s, 1H), 5.80(s, 2H), 4.66 (d, J=5.4 Hz, 2H), 3.90 (s, 3H), 2.04-1.93 (m, 1H),0.97-0.86 (m, 2H), 0.68-0.58 (m, 2H).

Example 255

Synthesis ofN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((7-cyclopropyl-5-hydroxy-[1,2,4]triazolo[1,5-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide

To a solution of1-((6-cyclopropylbenzofuran-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (100 mg, 0.33 mmol),(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride(85 mg, 0.36 mmol), EDCI (75 mg, 0.4 mmol) and HOBT (54 mg, 0.4 mmol) inDMF (5 mL) was added DIPEA (129 mg, 1 mmol). The resulting mixture wasstirred at RT for 15 h. The reaction mixture was concentrated to give aresidue. The residue was purified by flash column chromatography(DCM/MeOH=10/1) to giveN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((7-cyclopropyl-5-hydroxy-[1,2,4]triazolo[1,5-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(60 mg, 37.5%) as a pale-yellow solid. ESI-MS [M+H]⁺: 482.0.

Synthesis of1-((5-chloro-7-cyclopropyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)methyl)-N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(I-255)

A solution ofN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((7-cyclopropyl-5-hydroxy-[1,2,4]triazolo[1,5-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(40 mg, 0.08 mmol) in POCl₃ (10 mL) was stirred at 80° C. overnight. Themixture was concentrated under vacuum. The residue was poured intoNaHCO₃ (10 mL) and extracted with EtOAc (30 mL×2). The combined organiclayers were washed with brine, dried over Na₂SO₄, and concentrated togive the crude product. The residue was purified by flash columnchromatography (DCM/MeOH=10/1) to give1-((5-chloro-7-cyclopropyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)methyl)-N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(12 mg, 29%) as a pale-yellow solid. ESI-MS [M+H]⁺: 499.6. Purity:97.34% (214 nm), 97.80% (254 nm). ¹H NMR (400 MHz, CDCl3) S 8.23 (s,1H), 8.17 (s, 1H), 7.77-7.68 (m, 2H), 6.89 (s, 1H), 6.55 (s, 1H), 6.46(s, 1H), 5.80 (s, 2H), 4.97 (d, J=4.2 Hz, 2H), 2.07-1.98 (m, 1H),1.19-1.09 (m, 4H).

Example 256

Synthesis of Methyl 2-((5-bromopyridin-2-yl)(hydroxy)methyl)acrylate

To a solution of 5-bromopicolinaldehyde (1.5 g, 8.06 mmol) and DABCO (91mg, 0.81 mmol) in 1,4-dioxane (15 mL) and H₂O (5 mL) was added methylacrylate (2.08 g, 24.2 mmol). The resulting mixture was stirred in asealed tube at 60° C. overnight. The reaction mixture was concentratedto get a residue. The residue was purified by flash columnchromatography (0-18% EtOAc in Petroleum ether) to get the productmethyl 2-((5-bromopyridin-2-yl)(hydroxy)methyl)acrylate (1.8 g, 82%) asa yellow oil. ESI-MS [M+H]⁺: 271.7, ¹H NMR (400 MHz, CDCl₃) δ 8.61 (s,1H), 7.84 (dd, J=8.4, 1.9 Hz, 1H), 7.40 (d, J=8.4 Hz, 1H), 6.38 (s, 1H),6.00 (s, 1H), 5.59 (s, 1H), 3.74 (s, 3H).

Synthesis of Methyl 6-bromoindolizine-2-carboxylate

A solution of methyl 2-((5-bromopyridin-2-yl)(hydroxy)methyl)acrylate(1.8 g, 6.6 mmol) in Ac₂O (10 mL) was stirred at 100° C. for 5 h. LCMSshowed raw material conversion to an intermediate product. The reactionmixture was then stirred at 160° C. for 5 h. The mixture wasconcentrated to get a residue. The residue was purified by flash columnchromatography (0-5% EtOAc in Petroleum ether) to get the product methyl6-bromoindolizine-2-carboxylate (1.15 g, 68%) as a light yellow solid.ESI-MS [M+H]⁺: 253.7. ¹H NMR (400 MHz, CDCl₃) δ 8.02 (s, 1H), 7.75 (s,1H), 7.27 (d, J=7.5 Hz, 2H), 6.86 (s, 1H), 6.75 (d, J=9.5 Hz, 1H), 3.88(s, 3H).

Synthesis of Methyl 6-cyclopropylindolizine-2-carboxylate

A mixture of methyl 6-bromoindolizine-2-carboxylate (0.88 g, 3.46 mmol),cyclopropylboronic acid (740 mg, 8.66 mmol), Pd(OAc)₂ (79 mg, 0.35mmol), PCy₃ (196 mg, 0.7 mmol) and K₃PO₄ (1.84 g, 8.66 mmol) in toluene(30 mL)/H₂O (3 mL) was stirred under reflux under nitrogen atmosphereovernight. The reaction mixture was concentrated to get a residue. Theresidue was partitioned between EtOAc (30 mL) and H₂O (30 mL). Thelayers were separated and the aqueous phase was extracted with EtOAc(2×30 mL). The combined organic layers were washed with brine (20 mL),dried over Na₂SO₄, filtered and concentrated to get the crude product.The crude product was purified by flash column chromatography (0-5%EtOAc in Petroleum ether) to get the product methyl6-cyclopropylindolizine-2-carboxylate (660 mg, 88%) as a light yellowsolid. ESI-MS [M+H]⁺: 216.0. ¹H NMR (400 MHz, CDCl₃) δ 7.71 (s, 1H),7.65 (s, 1H), 7.25 (d, J=6.0 Hz, 2H), 6.75 (s, 1H), 6.44 (d, J=9.4 Hz,1H), 3.87 (s, 3H), 1.84-1.74 (m, 1H), 0.95-0.84 (m, 2H), 0.64 (t, J=5.1Hz, 2H).

Synthesis of (6-cyclopropylindolizin-2-yl)methanol

To a solution of methyl 6-cyclopropylindolizine-2-carboxylate (660 mg,3.1 mmol) in dry THF (25 mL) stirring at −70° C. under nitrogenatmosphere was added DIBAL-H (9.2 mL, 9.2 mmol) dropwise. The resultingmixture was stirred at −70° C. for 2 h. The reaction mixture wasquenched with saturated aqueous NH₄Cl solution (30 mL), extracted withEtOAc (3×30 mL). The combined organic phase was washed with brine (20mL), dried over Na₂SO₄, filtered and concentrated to get the crudeproduct. The crude product was purified by flash column chromatography(0-18% EtOAc in Petroleum ether) to get the product methyl6-cyclopropylindolizine-2-carboxylate (345 mg, 60%) as an off-whitesolid. ESI-MS [M+H]⁺: 187.9. ¹H NMR (400 MHz, CDCl₃) δ 7.66 (s, 1H),7.24-7.17 (m, 2H), 6.43 (d, J=9.3 Hz, 1H), 6.34 (s, 1H), 4.75 (s, 2H),1.88-1.71 (m, 1H), 0.95-0.78 (m, 2H), 0.69-0.56 (d, J=5.0 Hz, 2H).

Synthesis of 2-(azidomethyl)-6-cyclopropylindolizine

To a solution of methyl 6-cyclopropylindolizine-2-carboxylate (125 mg,0.67 mmol) and DPPA (239 mg, 0.87 mmol) in dry THF (8 mL) stirring atice H₂O bath was added DBU (132 mg, 0.87 mmol). The resulting mixturewas stirred at RT overnight. The reaction mixture was partitionedbetween EtOAc (50 mL) and H₂O (30 mL). The layers were separated and theaqueous phase was extracted with EtOAc (2×30 mL). The combined organicphase was washed with brine (15 mL), dried over Na₂SO₄, filtered andconcentrated to get the crude product. The crude product was purified bycolumn chromatography (Petroleum ether/EtOAc=100/1) to get the product2-(azidomethyl)-6-cyclopropylindolizine (120 mg, 84.5%) as a lightyellow oil. ESI-MS [M+H]⁺: 212.9.

Synthesis of Ethyl1-((6-cyclopropylindolizin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate

To a solution of 2-(azidomethyl)-6-cyclopropylindolizine (90 mg, 0.42mmol) in t-BuOH (3 mL) and H₂O (3 mL) was added sequentially ofCuSO₄-5H₂O (21 mg, 0.084 mmol), sodium ascorbate (25 mg, 0.126 mmol) andethyl propiolate (54 mg, 0.55 mmol). The resulting mixture was stirredat RT for 15 h. The reaction mixture was partitioned between DCM (20 mL)and H₂O (20 mL). The layers were separated and the aqueous phase wasextracted with DCM (2×30 mL). The combined organic phase was washed withbrine (15 mL), dried over Na₂SO₄, filtered and concentrated to get thecrude product. The crude product was purified by flash columnchromatography (0-50% EtOAc in Petroleum ether) to get the product ethyl1-((6-cyclopropylindolizin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(13 mg, 10%) as a light yellow solid. ESI-MS [M+H]⁺: 311.2.

Synthesis of1-((2-cyclopropylimidazo[1,2-a]pyridin-7-yl)methyl)-1H-1,2,3-triazole-4-carboxylicAcid

To a solution of ethyl1-((6-cyclopropylindolizin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(13 mg, 0.042 mmol) in THF (3 mL) was added a solution of NaOH (8 mg,0.2 mmol) in H₂O (3 mL). The mixture was stirred at RT for 1 h. THF wasremoved in vacuo and the pH of aqueous phase was acidified to 4-5 with2N HCl, lyophilized to give the product1-((6-cyclopropylindolizin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (25 mg, crude) as a yellow solid. ESI-MS [M+H]⁺: 283.0.

Synthesis ofN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylindolizin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(I-256)

To a mixture of1-((6-cyclopropylindolizin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (25 mg, crude from last step), EDCI (10 mg, 0.05 mmol), HOBT (7 mg,0.05 mmol) and DIPEA (16 mg, 0.126 mmol) in DMF (2 mL) was added(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine (10 mg, 0.042mmol). The resulting mixture was stirred at RT for 15 h. The reactionmixture was concentrated to get a residue. The residue was purified byprep-HPLC to getN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylindolizin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(5 mg, 25%) as an off-white solid. ESI-MS [M+H]⁺: 464.0. Purity: 98.76(214 nm), 98.85 (254 nm). ¹H NMR (400 MHz, CDCl3) δ 8.22 (s, 1H), 7.98(s, 1H), 7.79-7.67 (m, 2H), 7.65 (s, 1H), 7.24-7.15 (m, 2H), 6.54 (t,J=6.6 Hz, 1H), 6.47 (d, J=9.3 Hz, 1H), 6.27 (s, 1H), 5.60 (s, 2H), 4.96(d, J=5.2 Hz, 2H), 1.84-1.74 (m, 1H), 0.92-0.82 (m, 2H), 0.67-0.58 (m,2H).

Example 257

Synthesis of 2-methyl-5-(tributylstannyl)thiazole

To a solution of 2-methylthiazole (0.5 g, 5.1 mmol) in THF (15 mL) wasadded n-BuLi (2.4 M, 5 mL, 12 mmol) dropwise at −78° C. under N₂atmosphere. The reaction mixture was stirred for 1 h at −78° C., thenChlorotributyltin (1.98 g, 6.1 mmol) was added thereto. Then theresulting reaction was stirred for additional 1 h. The reaction wasquenched with H₂O (20 mL) and extracted with EtOAc (50 mL×2). Thecombined organic layers were washed with brine, dried over Na₂SO₄,concentrated to give the crude product, which was purified by silica gelchromatography (PE/EtOAc=10/1) to give the2-methyl-5-(tributylstannyl)thiazole as a colorless oil (1.3 g, yield:66%). ¹H NMR (400 MHz, CDCl₃) δ 7.59 (d, J=6.4 Hz, 1H), 2.78 (s, 3H),1.60-1.51 (m, 5H), 1.37-1.33 (m, 8H), 1.15-1.09 (m, 5H), 0.94-0.87 (m,9H).

Synthesis of tert-butyl1-((6-cyclopropyl-8-(2-methylthiazol-5-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate

To a solution of 2-methyl-5-(tributylstannyl)thiazole (360 mg, 0.93mmol) in toluene (15 mL) was added tert-butyl1-((8-bromo-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(325 mg, 0.78 mmol) and Pd(PPh₃)₄ (30 mg, 0.025 mmol) at RT. Theresulting mixture was stirred at 90° C. for 10 h under Ar atmosphere.The reaction was concentrated in vacuo to give the crude, which waspurified by silica gel chromatography (DCM/MeOH=10/1) to give tert-butyl1-((6-cyclopropyl-8-(2-methylthiazol-5-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(200 mg, yield: 50%) as a white solid. ESI-MS [M+H]⁺: 437.1.

Synthesis of1-((6-cyclopropyl-8-(2-methylthiazol-5-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicAcid

To the solution of tert-butyl1-((6-cyclopropyl-8-(2-methylthiazol-5-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate (170 mg, 0.39 mmol) in DCM (10mL) was added HCl (4 M solution in dioxane, 5 mL). The resultingreaction was stirred at RT for 10 h. The mixture was concentrated to get1-((6-cyclopropyl-8-(2-methylthiazol-5-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid (180 mg,crude) as a white solid, which was used into next step without furtherpurification. ESI-MS [M+H]⁺: 381.0

Synthesis ofN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(2-methylthiazol-5-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(I-257)

To a solution of1-((6-cyclopropyl-8-(2-methylthiazol-5-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid (180 mg crude) in 10 mL ofDMF was added EDCI (61 mg, 0.32 mmol) HOBT (43 mg, 0.32 mmol), DIPEA(168 mg, 1.3 mmol) and (7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride (76 mg, 0.32 mmol). The reaction mixture wasstirred at RT for 10 h. Water (30 mL) was added to the reaction andextracted with EtOAc (50 mL×3). The combined organic layers were washedwith brine, dried over Na₂SO₄, concentrated to give the crude product,which was purified by silica gel chromatography (DCM/MeOH=10/1) to giveN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(2-methylthiazol-5-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(102 mg, yield: 47%) as a white solid. ESI-MS [M+H]⁺: 561.7. Purity:95.50% (214 nm), 95.62% (254 nm). ¹H NMR (400 MHz, DMSO-d₆) δ 8.72 (t,J=5.1 Hz, 1H), 8.63-8.59 (m, 2H), 8.44 (s, 1H), 8.35 (s, 1H), 8.20 (d,J=7.4 Hz, 1H), 7.89 (s, 1H), 7.46 (s, 1H), 6.76 (t, J=6.8 Hz, 1H), 5.81(s, 2H), 4.70 (d, J=5.1 Hz, 2H), 2.69 (s, 3H), 2.02-1.95 (m, 1H),0.99-0.92 (m, 2H), 0.79-0.75 (m, 2H).

Example 258

Synthesis of1-((6-cyclopropyl-8-(3-methyl-1H-1,2,4-triazol-1-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicAcid

A mixture of tert-butyl1-((8-bromo-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(199 mg, 0.48 mmol), CuI (28.2 mg, 0.14 mmol), L-proline (34.6 mg, 0.29mmol), K₂CO₃ (199 mg, 1.44 mmol) and 3-methyl-4H-1,2,4-triazole (121 mg,1.44 mmol) in DMF (5 mL) was degassed by N₂ for 10 min and sealed tube.The resulting reaction mixture was heated to 110° C. for 60 h. Themixture was cooled to RT and concentrated to give the crude product,which was purified by prep-HPLC to obtain1-((6-cyclopropyl-8-(3-methyl-1H-1,2,4-triazol-1-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid as a white solid (16 mg, 9.2% yield). ESI-MS [M+H]⁺: 364.8.

Synthesis ofN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(3-methyl-1H-1,2,4-triazol-1-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(I-258)

A solution of1-((6-cyclopropyl-8-(3-methyl-4H-1,2,4-triazol-4-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (12 mg, 0.033 mmol) in anhydrous DMF (3 mL) was added(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride(7.7 mg, 0.033 mmol), DIPEA (8.5 mg, 0.066 mmol) and HATU (20 mg, 0.05mmol) in sequence. The mixture was stirred at RT for 14 h. The reactionwas diluted with H₂O (20 mL) and extracted with EtOAc (30 mL×3). Thecombined organic layers were washed with brine, dried over Na₂SO₄,concentrated to give the crude, which was purified by prep-HPLC toaffordN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(3-methyl-1H-1,2,4-triazol-1-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamideas pale a yellow solid (6.2 mg, 34%). ESI-MS [M+H]⁺: 546.1. Purity:100.00 (214 nm) 97.96 (254 nm). ¹H NMR (400 MHz, DMSO-d₆) δ 9.75 (s,1H), 8.70 (t, J=5.1 Hz, 1H), 8.67 (s, 1H), 8.42 (d, J=10.7 Hz, 2H), 8.19(d, J=7.3 Hz, 1H), 8.01 (s, 1H), 7.54 (s, 1H), 6.75 (t, J=6.9 Hz, 1H),5.82 (s, 2H), 4.69 (d, J=5.4 Hz, 2H), 2.40 (s, 3H), 2.09-2.01 (m, 1H),1.03-0.94 (m, 2H), 0.76-0.68 (m, 2H).

Example 259

Synthesis of4-(2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-5-cyclopropyl-1H-indol-1-yl)benzoicAcid (I-259)

A mixture of methyl2-(2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-5-cyclopropyl-1H-indol-1-yl)acetate(80 mg, 0.13 mmol) and LiOH.H₂O (28 mg, 0.67 mmol) in THF/H₂O (5 mL/2mL) was stirred at RT for 3 h. The pH of reaction mixture was adjustedto around 3 and white solid was precipitated. The mixture was filteredand the solid was washed with H₂O (5 mL×3). Then the solid wasfreeze-dried to give2-(2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-5-cyclopropyl-1H-indol-1-yl)aceticacid (54 mg, yield: 70%) as a white solid. ESI-MS [M+H]⁺: 584.1. Purity:97.25% (214 nm), 96.00% (254 nm). ¹H NMR (400 MHz, DMSO-d₆) δ 13.20 (s,1H), 8.65 (t, J=5.4 Hz, 1H), 8.44 (d, J=2.2 Hz, 1H), 8.28 (s, 1H), 8.20(d, J=7.4 Hz, 1H), 8.08 (d, J=8.4 Hz, 2H), 7.49 (d, J=8.4 Hz, 2H), 7.34(s, 1H), 7.00 (d, J=8.5 Hz, 1H), 6.91 (d, J=8.6 Hz, 1H), 6.75 (t, J=6.9Hz, 1H), 6.62 (s, 1H), 5.80 (s, 2H), 4.67 (d, J=5.4 Hz, 2H), 2.04-1.93(m, 1H), 0.96-0.88 (m, 2H), 0.67-0.60 (m, 2H).

Example 260

Synthesis of 4-(tert-butyl) 2-ethyl 1H-imidazole-2,4-dicarboxylate

To a mixture of ethyl (Z)-2-amino-2-(hydroxyimino)acetate (660 mg, 5mmol) and tert-butyl propiolate (694 mg, 5.5 mmol) in Xylene (10 mL) wasadded TEA (606 mg, 6 mmol). The mixture was stirred at 140° C. for 16 h.After cooled to RT, H₂O (25 mL) was added and the mixture was extractedwith EtOAc (35 mL×3). The combined organic layers were washed with brineand dried over Na₂SO₄, concentrated to give the crude, which waspurified by silica gel chromatography (PE/EA=1/1) to give 4-(tert-butyl)2-ethyl 1H-imidazole-2,4-dicarboxylate (400 mg, yield: 33%) as a yellowsolid. ESI-MS [M+H]⁺: 241.1.

Synthesis of 4-(tert-butyl) 2-ethyl1-((6-cyclopropylimidazo[1,2-a]541yridine-2-yl)methyl)-1H-imidazole-2,4-dicarboxylate

To a mixture of 4-(tert-butyl) 2-ethyl 1H-imidazole-2,4-dicarboxylate(240 mg, 1.0 mmol) and Cs₂CO₃ (1.0 g, 3.0 mmol) in DMF (10 mL) was added2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine (310 mg, 1.5 mmol).The reaction mixture was stirred at RT for 16 h. Water (40 mL) was addedto the reaction, extracted with EtOAc (40 mL×3). The combined organiclayers were washed with brine and dried over Na₂SO₄, concentrated togive the crude, which was purified by silica gel chromatography(DCM/MeOH=50/1 to 20/1) to give 4-(tert-butyl) 2-ethyl1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-imidazole-2,4-dicarboxylate(240 mg, yield: 59%) as a white solid. ESI-MS [M+H]⁺: 411.2.

Synthesis of1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-2-(ethoxycarbonyl)-1H-imidazole-4-carboxylicAcid

To the solution of 4-(tert-butyl) 2-ethyl1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-imidazole-2,4-dicarboxylate(240 mg, 0.6 mmol) in DCM (10 mL) was added TFA (1 mL). The mixture wasstirred at RT for 3 h. The reaction solution was concentrated to give1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-2-(ethoxycarbonyl)-1H-imidazole-4-carboxylicacid (250 mg crude) as yellow oil, which was used into next step withoutfurther purification. ESI-MS [M+H]⁺: 355.1.

Synthesis of Ethyl4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-imidazole-2-carboxylate(I-260)

To the mixture of1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-2-(ethoxycarbonyl)-1H-imidazole-4-carboxylicacid (250 mg, crude from previous step),(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride(170 mg, 0.72 mmol) and DIPEA (400 mg, 3.0 mmol) in DMF (5 mL) was addedHOBT (165 mg, 1.22 mmol) and EDCI (235 mg, 1.22 mmol). The reactionmixture was stirred at RT for 12 h. Water (40 mL) was added and themixture was extracted with EtOAc (45 mL×3). The combined organic layerswere washed with brine and dried over Na₂SO₄, concentrated to give thecrude, which was purified by Prep-TLC (DCM/MeOH=10/1) to give ethyl4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-imidazole-2-carboxylate(200 mg, yield: 61%) as a white solid. ESI-MS [M+H]⁺: 536.1. Purity:97.1% (214 nm), 96.4% (254 nm). ¹H NMR (400 MHz, DMSO-d₆) δ 8.64 (s,1H), 8.48 (s, 1H), 8.33 (t, J=5.5 Hz, 1H), 8.22 (d, J=7.4 Hz, 1H), 8.13(s, 1H), 8.05 (s, 1H), 7.78 (d, J=9.3 Hz, 1H), 7.63 (d, J=9.0 Hz, 1H),6.81-6.74 (m, 1H), 5.88 (s, 2H), 4.70 (d, J=5.6 Hz, 2H), 4.33 (q, J=7.1Hz, 2H), 2.10-2.04 (m, 1H), 1.29 (t, J=7.1 Hz, 3H), 1.10-0.95 (m, 2H),0.84-0.70 (m, 2H).

Example 261

Synthesis of4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-imidazole-2-carboxylicacid (I-261)

To the mixture of ethyl4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-imidazole-2-carboxylate(100 mg, 0.19 mmol) in EtOH/H₂O (8 mL/2 mL) was added LiOH.H₂O (24 mg,0.56 mmol). The resulting mixture was stirred at RT for 30 min. The pHof reaction was adjusted around 6 by HCl (1N), and then concentrated togive the crude, which was purified by Prep-HPLC to give4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-imidazole-2-carboxylicacid (30 mg, yield: 31%) as a white solid. ESI-MS [M−H]−: 506.0. Purity:83.9% (214 nm), 91.2% (254 nm). ¹H NMR (400 MHz, DMSO-d₆) δ 8.45 (d,J=2.4 Hz, 1H), 8.32 (s, 1H), 8.26-8.09 (m, 2H), 7.95 (s, 1H), 7.65 (s,1H), 7.39 (d, J=9.3 Hz, 1H), 7.00 (d, J=9.3 Hz, 1H), 6.80-6.71 (m, 1H),5.72 (s, 2H), 4.69 (d, J=5.5 Hz, 2H), 1.94-1.87 (m, 1H), 0.93-0.88 (m,2H), 0.69-0.56 (m, 2H).

Example 262

Synthesis of 5-cyclopropylpyridin-2-amine

To the solution of 4-bromopyridin-2-amine (5 g, 29.0 mmol) indioxane/H₂O (50 mL/5 mL) were added cyclopropylboronic acid (5 g, 58.0mmol), Pd(OAc)₂ (320 mg, 1.45 mmol), P(Cy)₃ (400 mg, 1.45 mmol) andK₃PO₄ (12 g, 58.0 mmol). The resulting reaction mixture was stirred at120° C. for 16 h under nitrogen. Then the mixture was concentrated invacuo. Water (400 mL) was added and the mixture was extracted with DCM(100 mL×3). The combined organic layers were washed with brine, driedover Na₂SO₄, concentrated to give the crude product, which was purifiedby silica gel chromatography (PE/EA=1/1) to give the5-cyclopropylpyridin-2-amine as a white solid (2.3 g, yield: 60%).ESI-MS [M+H]⁺: 135.1.

Synthesis of 2-bromo-4-cyclopropylpyridine

To a mixture of 5-cyclopropylpyridin-2-amine (800 mg, 6.0 mmol) in 48%HBr (20 mL) was add a solution of NaNO₂ (1.2 g, 18.0 mmol) in H₂O (10mL) at 0° C. The reaction was stirred at 0° C. for 30 min. Then Br₂ (2.9g, 18 mmol) was added thereto slowly at 0° C. The resulting mixture wasstirred at 0° C. for 4 h. The reaction solution was concentrated invacuo. H₂O (50 mL) was added to the residue, pH of the mixture wasadjusted to 7 by adding saturated NaHCO₃ solution, and then the mixturewas extracted with EtOAc (40 mL×3). The combined organic layers werewashed with brine, dried over Na₂SO₄, and concentrated to give the crudeproduct, which was purified by silica gel chromatography (PE/EA=10/1) togive 2-bromo-4-cyclopropylpyridine (770 mg, 65%) as a brown oil. ESI-MS[M+H]⁺: 197.9.

Synthesis of dimethyl7-bromo-5-cyclopropylpyrazolo[1,5-a]pyridine-2,3-dicarboxylate

To a solution of 2-bromo-4-cyclopropylpyridine (2 g, 10.1 mmol) in DCM(30 mL) was added O-(mesitylsulfonyl)hydroxylamine (4.6 g, 20.5 mmol) atRT and stirred at this temperature for 6 h. After evaporated to give thecrude intermediate, which was re-dissolved in MeCN (30 mL), DBU (3.1 g,20.5 mmol), dimethyl but-2-ynedioate (2.9 g, 20.5 mmol) was added at RT.The resulting mixture was stirred at RT for 7 h. The reaction wasconcentrated and purified by silica gel chromatography (PE/EA=5/1) togive dimethyl7-bromo-5-cyclopropylpyrazolo[1,5-a]pyridine-2,3-dicarboxylate (520 mg,14.5%) as a white solid. ESI-MS [M+H]⁺: 352.8

Synthesis of 7-bromo-5-cyclopropylpyrazolo[1,5-a]pyridine-2-carboxylicAcid

A mixture of dimethyl7-bromo-5-cyclopropylpyrazolo[1,5-a]pyridine-2,3-dicarboxylate (200 mg,0.57 mmol) and LiOH (47 mL, 1.14 mmol) in THF/H₂O (10 mL/2 mL) wasstirred at RT for 5 h. After evaporated, the mixture was re-dissolved in12 N HCl (2 mL) and dioxane (2 mL) at RT. The reaction mixture wasstirred at 100° C. for another 5 h. The pH value of reaction wasadjusted to 5 by adding saturated NaHCO₃ solution, and then extractedwith EtOAc (50 mL×3). The combined organic layers were washed withbrine, dried over Na₂SO₄, and concentrated to give the crude product,which was purified by silica gel chromatography (DCM/MeOH=5/1) to give7-bromo-5-cyclopropylpyrazolo[1,5-a]pyridine-2-carboxylic acid (100 mg,63%) as a white solid. ESI-MS [M+H]⁺: 280.9.

Synthesis of Methyl7-bromo-5-cyclopropylpyrazolo[1,5-a]pyridine-2-carboxylate

A mixture of 7-bromo-5-cyclopropylpyrazolo[1,5-a]pyridine-2-carboxylicacid (610 mg, 2.2 mmol), SOCl₂ (0.5 mL) in CH₃OH (10 mL) was stirred atRT for 16 h. The mixture was concentrated in vacuo to give the crude,which was purified by silica gel chromatography (PE/EA=5/1) to givemethyl 7-bromo-5-cyclopropylpyrazolo[1,5-a] pyridine-2-carboxylate (400mg, 62%) as a white solid. ESI-MS [M+H]⁺: 296.9.

Synthesis of (7-bromo-5-cyclopropylpyrazolo[1,5-a]pyridin-2-yl)methanol

To the solution of 7-bromo-5-cyclopropylpyrazolo[1,5-a]pyridine-2-carboxylate (200 mg, 0.68 mmol) in THF (15 mL) was addedLiBH₄ (28 mg, 1.36 mmol) at 0° C. and the mixture was stirred at RT for6 h. The reaction was quenched by the saturated aqueous NH₄Cl (320 mL),and extracted with EtOAc (35 mL×3). The combined organic layers werewashed with brine, dried over Na₂SO₄, and concentrated to give the crudeproduct, which was purified by silica gel chromatography (PE/EA=2/1) togive (7-bromo-5-cyclopropylpyrazolo[1,5-a]pyridin-2-yl)methanol (160 mg,89%) as a white oil. ESI-MS [M+H]⁺: 266.9.

Synthesis of2-(azidomethyl)-7-bromo-5-cyclopropylpyrazolo[1,5-a]pyridine

To the solution of(7-bromo-5-cyclopropylpyrazolo[1,5-a]pyridin-2-yl)methanol (150 mg, 0.56mmol) and DPPA (170 mg, 0.62 mmol) in toluene (7 mL) was added DBU (102mg, 0.67 mmol) at 0° C. The reaction mixture was stirred at RT for 16 h.Water (15 mL) was added and the mixture was extracted with DCM (30mL×3). The combined organic layers were concentrated and purified bysilica gel chromatography (PE/EA=10/1) to give2-(azidomethyl)-7-bromo-5-cyclopropylpyrazolo[1,5-a]pyridine (120 mg,73%) as a colorless oil. ESI-MS [M+H]⁺: 291.9.

Synthesis of Methyl1-((7-bromo-5-cyclopropylpyrazolo[1,5-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate

A mixture of2-(azidomethyl)-7-bromo-5-cyclopropylpyrazolo[1,5-a]pyridine (120 mg,0.41 mmol), methyl propiolate (52 mg, 0.62 mmol), CuSO₄.5H₂O (20 mg,0.08 mmol), NaVc (24 mg, 0.12 mmol) in t-BuOH/H₂O (4 mL/3 mL) wasstirred at RT for 16 h. The mixture was concentrated in vacuo to givethe crude product, which was purified by Prep-TLC to give methyl1-((7-bromo-5-cyclopropylpyrazolo[1,5-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(130 mg, 84%) as a white oil. ESI-MS [M]⁺: 375.8.

Synthesis of Methyl1-((5-cyclopropyl-7-(2-oxopyrrolidin-1-yl)pyrazolo[1,5-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate

To the solution of methyl1-((7-bromo-5-cyclopropylpyrazolo[1,5-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(90 mg, 0.24 mmol) in dioxane (10 mL) were added pyrrolidin-2-one (30mg, 0.36 mmol), Pd₂(dba)₃ (27 mg, 0.03 mmol), XantPhos (29 mg, 0.05mmol) and Cs₂CO₃ (162 mg, 0.5 mmol). The reaction mixture was stirred at120° C. for 1 h under nitrogen under microwave conditions. Then themixture was concentrated in vacuo. Water (40 mL) was added to theresidue and extracted with DCM (70 mL×3). The combined organic layerswere concentrated to give the crude product, which was purified bysilica gel chromatography (PE/EA=1/4) to give the methyl1-((5-cyclopropyl-7-(2-oxopyrrolidin-1-yl)pyrazolo[1,5-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylateas a white solid (40 mg, 44%). ESI-MS [M+H]⁺: 381.1.

Synthesis of1-((5-cyclopropyl-7-(2-oxopyrrolidin-1-yl)pyrazolo[1,5-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicAcid

A mixture of ethyl1-((5-cyclopropyl-1H-indol-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(40 mg, 0.1 mmol), LiOH.H₂O (9 mg, 0.2 mmol) in THF/EtOH/H₂O (2 mL/2mL/2 mL) was stirred at RT for 0.5 h. The pH of reaction mixture wasacidified by HCl (1N), concentrated in vacuo to give the crude product,which was washed by ether to give1-((5-cyclopropyl-7-(2-oxopyrrolidin-1-yl)pyrazolo[1,5-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (50 mg, crude) as a white solid. ESI-MS [M+H]⁺: 367.2.

Synthesis ofN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((5-cyclopropyl-7-(2-oxopyrrolidin-1-yl)pyrazolo[1,5-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(I-262)

A mixture of1-((5-cyclopropyl-7-(2-oxopyrrolidin-1-yl)pyrazolo[1,5-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (50 mg, crude),(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride(19 mg, 0.08 mmol), EDCI (17 mg, 0.09 mmol), HOBT (12 mg, 0.09 mmol),DIPEA (26 mg, 0.2 mmol) in DMF (3 mL) was stirred at RT for 16 h. H₂O(20 mL) was added to the reaction, extracted with EtOAc (30 mL×5). Thecombined organic layers were washed with brine, dried over Na₂SO₄,concentrated to give the crude, which was purified by Prep-TLC to giveN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((5-cyclopropyl-7-(2-oxopyrrolidin-1-yl)pyrazolo[1,5-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(3 mg, yield: 5%) as a white solid. ESI-MS [M+H]⁺: 547.8. Purity: 99.82%(214 nm), 99.61% (254 nm). ¹H NMR (400 MHz, CDCl₃) δ 8.39 (s, 1H), 8.13(s, 1H), 7.84 (s, 1H), 7.77 (s, 1H), 7.11 (s, 1H), 6.60-6.56 (m, 2H),6.34 (s, 1H), 5.72 (s, 2H), 4.98 (s, 2H), 4.04 (t, J=6.8 Hz, 2H), 2.65(t, J=8.0 Hz, 2H), 2.35-2.25 (m, 2H), 1.94-1.88 (m, 1H), 1.04-1.02 (m,2H), 0.77-0.76 (m, 2H).

Example 263

Synthesis of tert-butyl thiazole-2-carboxylate

To the solution of thiazole-2-carboxylic acid (300 mg, 2.3 mmol) in THF(6 mL) was added (COCl)₂ (590 mg, 4.6 mmol) and DMF (0.1 mL). Thereaction mixture was stirred at RT for 5 h and then t-BuOK (386 mg, 3.5mmol) was added thereto. The reaction mixture was stirred at RT for 1 h.The reaction was quenched with saturated aqueous NH₄Cl (20 mL),extracted with EtOAc (40 mL×3). The combined organic layers were washedwith brine, dried over Na₂SO₄, concentrated to give the crude product,which was purified by silica gel chromatography (PE/EA=1/2) to give thetert-butyl thiazole-2-carboxylate as a yellow solid (250 mg, yield:58%). ESI-MS [M+H]⁺: 186.0.

Synthesis of tert-butyl 5-(tributylstannyl)thiazole-2-carboxylate

To the solution of tert-butyl thiazole-2-carboxylate (510 mg, 2.7 mmol)in THF (40 mL) was added LDA (1.5 mL, 2 M, 3.0 mmol) at −100° C. Thereaction mixture was stirred at this temperature for 15 min and thenBu₃SnCl (980 mg, 3.0 mmol) was added. The reaction mixture was stirredfor 10 min at −100° C. for another 1 h. The reaction was quenched bysaturated aqueous NH₄Cl (15 mL), extracted with EtOAc (30 mL×3). Thecombined organic layers were washed with brine, dried over Na₂SO₄,concentrated to give the crude product, which was purified by silica gelchromatography (PE/EA=1/1) to give the tert-butyl5-(tributylstannyl)thiazole-2-carboxylate as a clear oil (900 mg, yield:69%).

Synthesis of tert-butyl5-(6-cyclopropyl-2-((4-(ethoxycarbonyl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-8-yl)thiazole-2-carboxylate

A mixture of tert-butyl 5-(tributylstannyl)thiazole-2-carboxylate (520mg, 1.1 mmol), ethyl1-((8-bromo-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(386 mg, 0.99 mmol), Pd(PPh₃)₄ (127 mg, 0.11 mmol) in toluene (10 mL)was stirred at 85° C. for 16 h under N₂. The mixture was concentrated togive the crude product, which was purified by silica gel chromatography((PE/EA=3/1)) to give tert-butyl5-(6-cyclopropyl-2-((4-(ethoxycarbonyl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-8-yl)thiazole-2-carboxylate(290 mg, yield: 59%) as a red oil. ESI-MS [M+H]⁺: 494.9.

Synthesis of1-((8-(2-(tert-butoxycarbonyl)thiazol-5-yl)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicAcid

A mixture of tert-butyl5-(6-cyclopropyl-2-((4-(ethoxycarbonyl)-1H-1,2,3-triazol-1-yl) methyl)imidazo[1,2-a]pyridin-8-yl)thiazole-2-carboxylate (190 mg, 0.38 mmol),LiOH (24 mg, 0.57 mmol) in THF/H₂O (5 mL/5 mL) was stirred at RT for 0.5h. The reaction solution was concentrated in vacuo to give1-((8-(2-(tert-butoxycarbonyl)thiazol-5-yl)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid as a white solid, which was used into next step without furtherpurification (210 mg crude). ESI-MS [M+H]⁺: 466.9

Synthesis of tert-butyl5-(2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)thiazole-2-carboxylate

A mixture of1-((8-(2-(tert-butoxycarbonyl)thiazol-5-yl)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (105 mg, crude from previous step),(7-chloroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride (50 mg,0.21 mmol), EDCI (42 mg, 0.24 mmol), HOBT (32 mg, 0.24 mmol) and DIPEA(69 mg, 0.54 mmol) in DMF (7 mL) was stirred at RT for 16 h. H₂O (30 mL)was added to the reaction, extracted with EtOAc (50 mL×3). The combinedorganic layers were washed with brine, dried over Na₂SO₄, concentratedin vacuo to give the crude, which was purified by Prep-TLC to givetert-butyl 5-(2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)thiazole-2-carboxylate(80 mg, yield: 65% over 2 steps) as a white solid. ESI-MS [M+H]⁺: 647.5.

Synthesis ofN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(thiazol-5-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(I-263)

To the mixture of tert-butyl 5-(2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)thiazole-2-carboxylate(50 mg, 0.077 mmol) in dioxane (5 mL) was added HCl (4 M solution indioxane, 3 mL). The resulting reaction was stirred at RT for 16 h. Themixture was concentrated and the residue was diluted with DCM/MeOH (30mL, 10/1 (v/v)), washed with H₂O (10 mL). The organic layer wasseparated, dried over Na₂SO₄, and concentrated in vacuo to give thecrude product, which was purified by Prep-TLC to giveN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(thiazol-5-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(10 mg, yield: 23.7%) as a white solid. ESI-MS [M+H]⁺: 547.8. Purity:100.00 (214 nm), 100.00 (254 nm). ¹H NMR (400 MHz, DMSO-d₆) δ 9.15 (s,1H), 8.88 (s, 1H), 8.70 (t, J=5.3 Hz, 1H), 8.62 (s, 1H), 8.44 (d, J=2.1Hz, 1H), 8.38 (s, 1H), 8.20 (d, J=7.4 Hz, 1H), 7.91 (s, 1H), 7.56 (s,1H), 6.75 (t, J=6.9 Hz, 1H), 5.82 (s, 2H), 4.70 (d, J=5.4 Hz, 2H),2.05-1.95 (m, 1H), 1.01-0.92 (m, 2H), 0.82-0.75 (m, 2H).

Example 264

Synthesis of Ethyl4-(2-((4-(tert-butoxycarbonyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)morpholine-2-carboxylate

To the mixture of tert-butyl1-((8-bromo-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(100 mg, 0.24 mmol), ethyl morpholine-2-carboxylate (114 mg, 0.72 mmol)and Cs₂CO₃ (235 mg, 0.72 mmol) in Dioxane (5 mL) was added Pd₂(dba)₃ (22mg, 0.024 mmol) and XantPhos (28 mg, 0.048 mmol). The mixture wasstirred at 100° C. for 16 h. Water (30 mL) was added to the reaction,extracted with EtOAc (30 mL×3), concentrated to give the crude, whichwas purified by Prep-TLC (EA/PE=2/1) to give ethyl4-(2-((4-(tert-butoxycarbonyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)morpholine-2-carboxylate(60 mg, yield: 50%) as a yellow solid. ESI-MS [M+H]⁺: 497.2

Synthesis of1-((6-cyclopropyl-8-(2-(ethoxycarbonyl)morpholino)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicAcid

A mixture of ethyl4-(2-((4-(tert-butoxycarbonyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)morpholine-2-carboxylate(60 mg, 0.12 mmol) in dioxane (2 mL) was added HCl (4 M solution indoxane, 1 mL). The resulting reaction was stirred at 25° C. for 2 h. Thereaction was concentrated to give1-((6-cyclopropyl-8-(2-(ethoxycarbonyl)morpholino)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (65 mg, yield: 100%) as a yellow solid, which was used into nextstep without further purification. ESI-MS [M+H]⁺: 441.2.

Synthesis of Ethyl4-(2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)morpholine-2-carboxylate

To the mixture of1-((6-cyclopropyl-8-(2-(ethoxycarbonyl)morpholino)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (65 mg, from previous step),(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride(43 mg, 0.18 mmol), HOBT (33 mg, 0.24 mmol), EDCI (46 mg, 0.24 mmol) inDMF (5 mL) was added DIPEA (93 mg, 0.72 mmol). The reaction mixture wasstirred at 25° C. for 16 h. Water (30 mL) was added to the reaction,extracted with EtOAc (30 mL×3). The combined organic layers were washedwith brine, dried over Na₂SO₄, concentrated to give the crude product,which was purified with Prep-TLC (DCM/MeOH=10/1) to offer ethyl4-(2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)morpholine-2-carboxylate(70 mg, yield: 93%) as a yellow solid. ESI-MS [M+H]⁺: 622.2.

Synthesis of4-(2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)morpholine-2-carboxylicacid (I-264)

To the mixture of ethyl4-(2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)morpholine-2-carboxylate(70 mg, 0.11 mmol) in THF/H₂O (2/2 mL) was added LiOH (8.1 mg, 0.33mmol). The mixture was stirred at 25° C. for 2 h. The pH of reaction wasadjusted by HCl (1N), concentrated to give the crude, purified byPrep-HPLC to give4-(2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)morpholine-2-carboxylicacid (20.4 mg, yield: 30%) as a white solid. ESI-MS [M+H]⁺: 594.2.Purity: 98.05% (214 nm), 97.76% (254 nm). ¹H NMR (400 MHz, DMSO-d₆) δ8.74 (t, J=5.5 Hz, 1H), 8.54 (s, 1H), 8.45 (d, J=2.4 Hz, 1H), 8.21 (d,J=7.4 Hz, 1H), 7.94 (s, 1H), 7.71 (s, 1H), 6.78-6.76 (m, 1H), 6.26 (s,1H), 5.72 (s, 2H), 4.70 (d, J=5.5 Hz, 2H), 4.26-4.24 (m, 1H), 4.14-4.11(m, 1H), 4.05-4.03 (m, 1H), 3.87-3.84 (m, 1H), 3.75-3.70 (m, 1H),3.77-3.06 (m, 1H), 2.99-2.94 (m, 1H), 1.91-1.85 (m, 1H), 0.90-0.85 (m,2H), 0.69-0.65 (m, 2H).

Example 265

Synthesis of 8-bromo-2-(bromomethyl)-6-chloroimidazo[1,2-b]pyridazine

A mixture of 4-bromo-6-chloropyridazin-3-amine (13.0 g, 62.5 mmol) and1,3-dibromopropan-2-one (40.5 g, 187.5 mmol) in DME (100 mL) was stirredat 90° C. for 16 h. The reaction was quenched with saturated aqueousNaHCO₃ (100 mL), extracted with EtOAc (100 mL×3). The combined organiclayers were washed with brine, dried over Na₂SO₄, concentrated to givethe crude, which was purified by silica gel chromatography (PE/EA=15/1)to give 8-bromo-2-(bromomethyl)-6-chloroimidazo[1,2-b]pyridazine (13.5g, yield: 66.5%) as a yellow solid. ESI-MS [M+H]⁺: 325.9.

Synthesis of 2-(azidomethyl)-8-bromo-6-chloroimidazo[1,2-b]pyridazine

To the solution of8-bromo-2-(bromomethyl)-6-chloroimidazo[1,2-b]pyridazine (7.5 g, 23.1mmol) in DMF (30 mL) was added NaN₃ (2.0 g, 30.0 mmol). The resultingreaction was stirred at 25° C. for 3 h. H₂O (80 mL) was added to thereaction, extracted with EtOAc (60 mL×3). The combined organic layerswere washed with brine, dried over Na₂SO₄, concentrated to give2-(azidomethyl)-8-bromo-6-chloroimidazo[1,2-b]pyridazine (5.1 g, yield:77%) as a yellow solid, which was used into next step without furtherpurification. ESI-MS [M+H]⁺: 286.0.

Synthesis of tert-butyl1-((8-bromo-6-chloroimidazo[1,2-b]pyridazin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate

To the solution of2-(azidomethyl)-8-bromo-6-chloroimidazo[1,2-b]pyridazine (5.1 g, 17.8mmol) was added tert-butyl propiolate (6.7 g, 53.4 mmol), CuSO₄ (0.6 g,3.6 mmol), sodium ascorbate (0.7 g, 3.6 mmol) in t-BuOH (15 mL) and H₂O(15 mL). The resulting mixture was stirred at 25° C. for 16 h. Thesolvent was concentrated to give the crude, which was purified by silicagel chromatography (DCM/MeOH=20/1) to give tert-butyl1-((8-bromo-6-chloroimidazo[1,2-b]pyridazin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(3.5 g, yield: 47%) as a yellow solid. ESI-MS [M+H]⁺: 413.1

Synthesis of tert-butyl1-((6-chloro-8-(3-(methoxycarbonyl)azetidin-1-yl)imidazo[1,2-b]pyridazin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate

To the solution of tert-butyl1-((8-bromo-6-chloroimidazo[1,2-b]pyridazin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(600 mg, 1.5 mmol) in acetonitrile (20 mL) was added methylazetidine-3-carboxylate (300 mg, 2.3 mmol) and DIPEA (600 mg, 4.5 mmol).The mixture was stirred at 100° C. for 2 h. Water (50 mL) was added tothe reaction, extracted with EtOAc (50 mL×3). The combined organiclayers were washed with brine, dried over Na₂SO₄, filtered andconcentrated to give the crude, which was purified by silica gelchromatography (PE/EA=1/1) to give tert-butyl1-((6-chloro-8-(3-(methoxycarbonyl)azetidin-1-yl)imidazo[1,2-b]pyridazin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(550 mg, yield: 82%) as a yellow solid. ESI-MS [M+H]⁺: 448.2.

Synthesis of tert-butyl1-((6-cyclopropyl-8-(3-(methoxycarbonyl)azetidin-1-yl)imidazo[1,2-b]pyridazin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate

To the solution of tert-butyl1-((6-chloro-8-(3-(methoxycarbonyl)azetidin-1-yl)imidazo[1,2-b]pyridazin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(550 mg, 1.2 mmol) and cyclopropylboronic acid (320 mg, 3.69 mmol) intoluene (20 mL) and H₂O (2 mL) was added K₃PO₄ (900 mg, 4.3 mmol), SPhos(50 mg, 0.12 mmol) and Pd(OAc)₂ (30 mg, 0.12 mmol). After the mixturewas stirred at 90° C. for 8 h under N₂. Water (40 mL) was added andextracted with EtOAc (40 mL×3). The combined organic layers were washedwith brine, dried over Na₂SO₄, concentrated to give the crude, which waspurified by silica gel chromatography (DCM/MeOH=20/1) to give tert-butyl1-((6-cyclopropyl-8-(3-(methoxycarbonyl)azetidin-1-yl)imidazo[1,2-b]pyridazin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(550 mg, yield: 98.7%) as a yellow solid. ESI-MS [M+H]⁺: 454.2.

Synthesis of1-((6-cyclopropyl-8-(3-(methoxycarbonyl)azetidin-1-yl)imidazo[1,2-b]pyridazin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicAcid

To a solution of tert-butyl1-((6-cyclopropyl-8-(3-(methoxycarbonyl)azetidin-1-yl)imidazo[1,2-b]pyridazin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(550 mg, 1.2 mmol) in DCM (10 mL) was added TFA (3 mL). The resultingreaction mixture was stirred at 25° C. for 3 h. The reaction wasconcentrated to give the crude1-((6-cyclopropyl-8-(3-(methoxycarbonyl)azetidin-1-yl)imidazo[1,2-b]pyridazin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (600 mg crude) as a black solid, which was used into next stepwithout further purification. ESI-MS [M+H]⁺: 398.1.

Synthesis of Methyl1-(2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-b]pyridazin-8-yl)azetidine-3-carboxylate(I-265a)

To the solution of1-((6-cyclopropyl-8-(3-(methoxycarbonyl)azetidin-1-yl)imidazo[1,2-b]pyridazin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (600 mg, crude from previous step) was added(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride(470 mg, 2.0 mmol), HOBT (270 mg, 2.0 mmol), EDCI (380 mg, 2.0 mmol) andDIPEA (500 mg, 3.9 mmol) in DMF (20 mL). The mixture was stirred at 25°C. for 3 h. H₂O (50 mL) was added to the reaction, extracted with EtOAc(100 mL×3), combined organic layers were concentrated to give the crude,which was purified by silica gel chromatography (DCM/MeOH=10/1) to givemethyl1-(2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-b]pyridazin-8-yl)azetidine-3-carboxylate(350 mg, yield: 50%) as a pale solid. ESI-MS [M+H]⁺: 579.1. Purity:95.43% (214 nm), 95.27 (254 nm). ¹H NMR (400 MHz, DMSO-d₆) δ 8.68 (t,J=5.4 Hz, 1H), 8.51 (s, 1H), 8.44 (d, J=2.4 Hz, 1H), 8.20 (d, J=7.4 Hz,1H), 7.94 (s, 1H), 6.80-6.71 (m, 1H), 5.72 (s, 1H), 5.66 (s, 2H), 4.69(d, J=5.5 Hz, 2H), 4.49 (s, 2H), 4.36 (s, 2H), 3.74-3.62 (m, 4H),2.00-1.90 (m, 1H), 0.98-0.83 (m, 4H).

Synthesis of1-(2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-b]pyridazin-8-yl)azetidine-3-carboxylicacid (I-265b)

To the solution of methyl1-(2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-b]pyridazin-8-yl)azetidine-3-carboxylate(150 mg, 0.26 mmol) in THF/H₂O (4 mL/4 mL) was added LiOH (32 mg, 0.77mmol). The mixture was stirred for 3 h at 25° C. The pH of the reactionwas adjusted by HCl (1N), and white solid was precipitated. The mixturewas filtered, and the cake was dried to give1-(2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-b]pyridazin-8-yl)azetidine-3-carboxylicacid (46 mg, yield: 31.4%) as a white solid. ESI-MS [M+H]⁺: 565.2.Purity: 95.74% (214 nm), 95.45% (254 nm). ¹H NMR (400 MHz, DMSO-d₆) δ8.68 (t, J=5.5 Hz, 1H), 8.51 (s, 1H), 8.44 (d, J=2.4 Hz, 1H), 8.20 (d,J=7.4 Hz, 1H), 7.93 (s, 1H), 6.79-6.73 (m, 1H), 5.70 (s, 1H), 5.67 (s,2H), 4.70 (d, J=5.5 Hz, 2H), 4.46 (s, 2H), 4.34 (s, 2H), 3.61-3.53 (m,1H), 1.98-1.90 (m, 1H), 0.95-0.85 (m, 4H).

Example 266

Synthesis of tert-butyl1-((6-chloro-8-(3-(methoxycarbonyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate

To a solution of tert-butyl1-((8-bromo-6-chloroimidazo[1,2-b]pyridazin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(300 mg, 0.73 mmol), methyl pyrrolidine-3-carboxylate hydrochloride (725mg, 4.38 mmol) and DIPEA, (723 mg, 5.11 mmol) in acetonitrile (10 mL).The mixture was stirred at 100° C. for 1 h. The reaction was quenchedwith saturated aqueous NH₄Cl, extracted with DCM (50 mL×3). The combinedorganic layers were washed with brine, dried over Na₂SO₄, concentratedto give the crude, which was purified by silica gel chromatography(MeOH/DCM=1/30) to give tert-butyl1-((6-chloro-8-(3-(methoxycarbonyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(250 mg, yield: 74.6%) as a white solid. ESI-MS [M+H]⁺: 462.1

Synthesis of tert-butyl1-((6-cyclopropyl-8-(3-(methoxycarbonyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate

To the solution of tert-butyl1-((6-chloro-8-(3-(methoxycarbonyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(250 mg, 0.54 mmol), cyclopropylboronic acid (140 mg, 1.62 mmol), SPhos(22 mg, 0.05 mmol), Pd(OAc)₂ (12 mg, 0.05 mmol) and K₃PO₄ (345 mg, 1.62mmol) in toluene/H₂O (10 mL/1 mL). The mixture was stirred at 90° C. for16 h. The reaction was concentrated to give the crude, which waspurified by silica gel chromatography (MeOH/DCM=1/20) to give tert-butyl1-((6-cyclopropyl-8-(3-(methoxycarbonyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-2yl)methyl)-1H-1,2,3-triazole-4-carboxylate(200 mg, yield: 79.0%) as a white solid. ESI-MS [M+H]⁺: 468.2

Synthesis of1-((6-cyclopropyl-8-(3-(methoxycarbonyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicAcid

To the solution tert-butyl1-((6-cyclopropyl-8-(3-(methoxycarbonyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(200 mg, 0.43 mmol) in DCM (5 mL) was added TFA (1 mL). The resultingmixture was stirred at 25° C. for 2 h. The reaction was concentrated togive1-((6-cyclopropyl-8-(3-(methoxycarbonyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (210 mg, crude) as yellow oil, which was used into next stepwithout further purification. ESI-MS [M+H]⁺: 412.1

Synthesis of Methyl1-(2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-b]pyridazin-8-yl)pyrrolidine-3-carboxylate(I-266)

To the solution of1-((6-cyclopropyl-8-(3-(methoxycarbonyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (210 mg, crude from previous step),(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride(132 mg, 0.56 mmol) in DMF (10 mL) was added HOBT (104 mg, 0.77 mmol),EDCI (148 mg, 0.77 mmol) and DIPEA (300 mg, 2.28 mmol). The resultingreaction mixture was stirred at 25° C. for 16 h. H₂O (40 mL) was addedto the reaction, extracted with EtOAc (50 mL×3). The combined organiclayers were washed with brine, dried over Na₂SO₄, concentrated to givethe crude, which was purified by Prep-HPLC to give methyl1-(2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-b]pyridazin-8-yl)pyrrolidine-3-carboxylate(70 mg, yield: 26% over 2 steps) as a white solid. ESI-MS [M+H]⁺: 593.2.Purity: 99.08% (214 nm), 99.10% (254 nm). ¹H NMR (400 MHz, DMSO-d₆) δ8.68 (t, J=5.4 Hz, 1H), 8.50 (s, 1H), 8.44 (d, J=2.3 Hz, 1H), 8.20 (d,J=7.4 Hz, 1H), 7.93 (s, 1H), 6.76 (t, J=6.9 Hz, 1H), 5.77 (s, 1H), 5.67(s, 2H), 4.69 (d, J=5.5 Hz, 2H), 4.01 (s, 2H), 3.81 (s, 2H), 3.65 (s,3H), 3.29 (s, 1H), 2.27-2.19 (m, 1H), 2.19-2.10 (m, 1H), 2.00-1.91 (m,1H), 0.94-0.86 (m, 4H).

Example 267

Synthesis of1-(2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-b]pyridazin-8-yl)pyrrolidine-3-carboxylicacid (I-267)

To the solution of methyl1-(2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-b]pyridazin-8-yl)pyrrolidine-3-carboxylate(56 mg, 0.09 mmol) in THF/H₂O (4 mL/2 mL) was added LiOH.H₂O (12 mg,0.28 mmol). The reaction mixture was stirred at 25° C. for 2 h, The pHof reaction was adjusted to 4 by HCl (1N) and the mixture wereconcentrated to give the crude, which was purified by Prep-HPLC to give1-(2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-b]pyridazin-8-yl)pyrrolidine-3-carboxylicacid (15 mg, yield: 28%) as a white solid. ESI-MS [M+H]⁺: 579.1. Purity:92.22% (214 nm), 95.13% (254 nm). ¹H NMR (400 MHz, DMSO-d₆) S=8.68 (s,1H), 8.50 (s, 1H), 8.44 (s, 1H), 8.20 (d, J=7.3, 1H), 7.92 (s, 1H), 6.76(t, J=7.2 Hz, 1H), 5.75-5.67 (m, 2H), 4.69 (d, J=5.4, 2H), 4.00 (s, 2H),3.77 (s, 2H), 3.12 (s, 1H), 2.17-1.95 (m, 3H), 0.98-0.89 (m, 4H).

Example 268

Synthesis of 5-cyclopropylpicolinaldehyde

A mixture of 5-chloropicolinaldehyde (10.0 g, 71 mmol),cyclopropylboronic acid (8.5 g, 99 mmol), Pd(OAc)₂ (1.6 g, 7.1 mmol),SPhos (5.8 g, 14.2 mmol) and K₃PO₄ (45 g, 213 mmol) in toluene (200 mL)and H₂O (30 mL) was stirred at 100° C. for 16 h. Toluene was evaporated,H₂O (100 mL) was added and extracted by EtOAc (100 mL×3). The combinedorganic layers were washed by H₂O and brine, dried over Na₂SO₄, filteredand concentrated to crude, which was purified by column chromatographyon silica gel (PE:EA=5:1) to give the 5-cyclopropylpicolinaldehyde (7.4g, yield: 71%), as a white solid. ESI-MS [M+H]⁺: 148.1

Synthesis of Methyl2-((5-cyclopropylpyridin-2-yl)(hydroxy)methyl)acrylate

A solution of 5-cyclopropylpicolinaldehyde (7.4 g, 50 mmol), ethylacrylate (20 g, 200 mmol) and Dabco (5.6 g, 50 mmol) in 1,4-dioxane (100mL) and H₂O (100 mL) was stirred at RT for 4 h. Water (50 mL) was addedto the reaction and extracted by EtOAc (100 mL×3). The combined organiclayers were washed by brine, dried over Na₂SO₄ and concentrated to givecrude, which was purified by column chromatography on silica gel(PE:EA=3:1) to give methyl2-((5-cyclopropylpyridin-2-yl)(hydroxy)methyl)acrylate (10.4 g, 84%),ESI-MS [M+H]⁺: 248.1

Synthesis of Ethyl 6-cyclopropylindolizine-2-carboxylate

A mixture of 2-((5-cyclopropylpyridin-2-yl)(hydroxy)methyl)acrylate (9.4g, 38.0 mmol) in Ac₂O (100 mL) was stirred at 130° C. for 1 h. Then Ac₂Owas removed under reduce press to give the crude, which was purified bycolumn chromatography on silica gel (PE:EA=10:1) to obtain ethyl6-cyclopropylindolizine-2-carboxylate (5.49 g, yield: 63.0%). ESI-MS[M+H]⁺: 230.1

Synthesis of Ethyl 3-chloro-6-cyclopropylindolizine-2-carboxylate

A mixture of ethyl 6-cyclopropylindolizine-2-carboxylate (1.5 g, 6.6mmol) and NCS (1.05 g, 7.9 mmol) in CH₃CN (30 mL) was stirred at RT for2 h. Then saturated aqueous NaHCO₃ was added to the reaction, extractedwith EtOAc (70 mL×3). The combined organic layers were washed withbrine, dried over Na₂SO₄, filtered, and concentrated to give the crude,which was purified by column chromatography on silica gel (PE:EA=20:1)to give ethyl 3-chloro-6-cyclopropylindolizine-2-carboxylate (900 mg,yield: 52%). ESI-MS [M+H]⁺: 264.1

Synthesis of (3-chloro-6-cyclopropylindolizin-2-yl)methanol

A mixture of ethyl 3-chloro-6-cyclopropylindolizine-2-carboxylate (1.5g, 5.7 mmol) in THF (25 mL) was added DIBAL-H (14 mL, 1 M, 14.25 mmol)dropwise at 0° C. The reaction was stirred at 0° C. for 2 h. Thereaction was quenched with NH₄Cl solution (30 mL) and extracted withEtOAc (50 mL×3). The combined organic layers were concentrated to give(3-chloro-6-cyclopropylindolizin-2-yl)methanol (1 g, crude), which wasused into next step without further purification. ESI-MS [M+H]⁺: 222.1

Synthesis of Ethyl 6-cyclopropyl-2-(hydroxymethyl)indolizine-3-carboxylate

A mixture of (3-chloro-6-cyclopropylindolizin-2-yl)methanol (1 g,crude), Pd(dppf)Cl₂ (329 mg, 0.45 mmol) and TEA (1.36 g, 13.5 mmol) inEtOH (40 mL) was refluxed under CO for 24 h. The reaction wasconcentrated to give the crude, which was purified by columnchromatography on silica gel (PE:EA=10:1) to obtain ethyl6-cyclopropyl-2-(hydroxymethyl) indolizine-3-carboxylate (248 mg, yield:17% over 2 steps). ESI-MS [M+H]⁺: 260.1

Synthesis of Ethyl 2-(azidomethyl)-6-cyclopropylindolizine-3-carboxylate

To a mixture of ethyl 6-cyclopropyl-2-(hydroxymethyl)indolizine-3-carboxylate (248 mg, 0.95 mmol) and DPPA (790 mg, 2.87mmol) in DCM (8.0 mL) was added DBU (436 mg, 2.87 mmol) dropwise at 0°C. The resulting mixture was stirred at RT for 16 h. The reaction wasconcentrated in vacuo to give the crude, which was purified by columnchromatography on silica gel (PE:EA=10:1), obtained ethyl2-(azidomethyl)-6-cyclopropylindolizine-3-carboxylate (203 mg, yield:75%). ESI-MS [M+H]⁺: 285.1

Synthesis of Ethyl2-((4-(tert-butoxycarbonyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylindolizine-3-carboxylate

A reaction mixture of ethyl2-(azidomethyl)-6-cyclopropylindolizine-3-carboxylate (203 mg, 0.71mmol), tert-butyl propiolate (120 mg, 0.94 mmol), CuSO₄ (150 mg, 0.94mmol) and sodium ascorbate (681 mg, 3.44 mmol) in t-BuOH (8 mL) and H₂O(4 mL) was stirred at RT for 16 h. H₂O (30 mL) was added to thereaction, extracted with EtOAc (30 mL×3). The combined organic layerswere dried by Na₂SO₄, filtered, and concentrated to give the crude,which was purified by column chromatography on silica gel (PE:EA=10:1)to obtain ethyl2-((4-(tert-butoxycarbonyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylindolizine-3-carboxylate(204 mg, yield: 70%). ESI-MS [M+H]⁺: 411.1

Synthesis of 1-((6-cyclopropyl-3-(ethoxycarbonyl)indolizin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic Acid

A reaction mixture of ethyl2-((4-(tert-butoxycarbonyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylindolizine-3-carboxylate(203 mg, 0.5 mmol) in HCl (2 M in 1,4-dioxane, 6 mL) and EtOAc (2 mL)was stirred at RT for 3 h. The reaction was concentrated to give thecrude, which was purified by Prep-HPLC to obtain1-((6-cyclopropyl-3-(ethoxycarbonyl)indolizin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid (41 mg,yield: 23%). ESI-MS [M+H]⁺: 355.1

Synthesis of Ethyl2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylindolizine-3-carboxylate(I-268)

A mixture of 1-((6-cyclopropyl-3-(ethoxycarbonyl)indolizin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid (41 mg, 0.12mmol), (7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanaminehydrochloride (49 mg, 0.21 mmol), HOBT (41 mg, 0.3 mmol), EDCI (58 mg,0.3 mmol), and DIPEA (77 mg, 0.6 mmol) in DMF (2 mL) was stirred at RTfor 16 h. Water (30 mL) was added to the reaction, extracted by EtOAc(30 mL×3). The combined organic layers were washed by brine, dried overNa₂SO₄, filtered, and concentrated to give the crude, which was purifiedby Prep-TLC (DCM:MeOH=10:1) to obtain ethyl2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylindolizine-3-carboxylate(28 mg, yield: 44%). ESI-MS [M+H]⁺: 536.1. Purity: 93.82% (214 nm),99.00% (254 nm). ¹H NMR (400 MHz, DMSO-d₆) δ 9.23 (s, 1H), 8.72 (t,J=6.0 Hz, 1H), 8.52 (s, 1H), 8.45 (d, J=4 Hz, 1H), 8.21 (d, J=8.0 Hz,1H), 7.56 (d, J=12 Hz, 1H), 6.92-6.89 (m, 1H), 6.76 (t, J=6.0 Hz, 1H),6.14 (s, 1H) 5.95 (s, 2H), 4.70 (d, J=4.0 Hz, 2H), 4.33 (q, J=6.6 Hz,2H), 2.02-1.97 (m, 1H), 1.31 (t, J=8 Hz, 3H), 0.97-0.94 (m, 2H),0.71-0.67 (m, 2H).

Example 269

Synthesis of Methyl 2,3-dimethyl-1H-indole-5-carboxylate

A mixture of 4-hydrazinylbenzoic acid (3.04 g, 20.0 mmol) andbutan-2-one (2.88 g, 40.0 mmol) in HCl/MeOH (5 mL/30 mL) was stirred at70° C. for 24 h. The mixture was concentrated and purified by silica gelcolumn chromatography (DCM/MeOH=40/1) to give methyl2,3-dimethyl-1H-indole-5-carboxylate (2.50 g, yield: 61.6%) as a yellowsolid. ESI-MS [M+H]⁺: 204.1

Synthesis of Methyl 1,2,3-trimethyl-1H-indole-5-carboxylate

To a mixture of methyl 2,3-dimethyl-1H-indole-5-carboxylate (2.3 g,11.33 mmol) in dry THF (25 mL) was added NaH (1.05 g, 60 wt %, 15.86mmol) at 0° C. After 0.5 h, MeI (0.85 mL, 13.60 mmol) in THF (5 mL) wasadded and stirred at RT for 3 h. The reaction was quenched with 2 M H₂O(50 mL) and the pH value was adjusted to 6. The mixture was extractedEtOAc (50 mL×3). The combined organic layers were concentrated andpurified by silica gel column chromatography (PE/EA=9/1) to give methyl1,2,3-trimethyl-1H-indole-5-carboxylate (1.80 g, 73%) as a yellow solid.ESI-MS [M+H]⁺: 218.1.

Synthesis of (1,2,3-trimethyl-1H-indol-5-yl)methanol

To a mixture of methyl 1,2,3-trimethyl-1H-indole-5-carboxylate (1.6 g,7.37 mmol) in dry THF (30 mL) was stirred LiAlH₄ (336.0 mg, 8.8 mmol) at0° C. under N₂. The mixture was stirred at 0° C. for 2 h. It wasquenched with H₂O (5 mL) and filtered. The filtrate was concentrated anddried to give (1,2,3-trimethyl-1H-indol-5-yl)methanol (1.4 g, crude) asa light yellow solid. ESI-MS [M+H]⁺: 190.1. It was used for the nextstep directly without purification.

Synthesis of 5-(azidomethyl)-1,2,3-trimethyl-1H-indole

To a mixture of (1,2,3-trimethyl-1H-indol-5-yl)methanol (800 mg, crude)and DPPA (2.7 mL, 12.70 mmol) in dry DCM (20.0 mL) was added DBU (1.9mL, 12.70 mmol) at 0° C. slowly. The mixture was stirred at RT for 18 h.Then diluted with DCM (50 mL) and washed with H₂O (50 mL). The organiclayer was concentrated and purified by silica gel column chromatography(PE/EA=10/1) to give 5-(azidomethyl)-1,2,3-trimethyl-1H-indole as ayellow solid. (350 mg). ESI-MS [M+H]⁺: 215.1.

Synthesis of Ethyl1-((1,2,3-trimethyl-1H-indol-5-yl)methyl)-1H-1,2,3-triazole-4-carboxylate

A mixture of 5-(azidomethyl)-1,2,3-trimethyl-1H-indole (350 mg, 1.63mmol), ethyl propiolate (208 mg, 2.13 mmol), CuSO₄ (130 mg, 0.82 mmol)and sodium ascorbate (162 mg, 0.82 mmol) in H₂O/t-BuOH (5.0 mL/5.0 mL)was stirred at RT for 3 h. The mixture was concentrated and purified byflash silica gel chromatography (DCM/MeOH=25/1) to give ethyl1-((1,2,3-trimethyl-1H-indol-5-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(250 mg, yield: 49%) as a yellow solid. ESI-MS [M+H]⁺: 313.1.

Synthesis of1-((1,2,3-trimethyl-1H-indol-5-yl)methyl)-1H-1,2,3-triazole-4-carboxylicAcid

A solution of ethyl1-((1,2,3-trimethyl-1H-indol-5-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(100.0 mg, 0.32 mmol) and LiOH.H₂O (40.3 mg, 0.96 mmol) in a mixedsolvent of THF/H₂O (2 mL/2 mL) was stirred at RT for 3 h. The pH valuewas adjusted to 3 by 1 M HCl solution and the white solid wasparticipated. The solid was filtered and dried to give1-((1,2,3-trimethyl-1H-indol-5-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (60.0 mg, yield: 66%) as a white solid. ESI-MS [M+H]⁺: 285.1.

Synthesis ofN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((1,2,3-trimethyl-1H-indol-5-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(I-269)

A mixture of1-((1,2,3-trimethyl-1H-indol-5-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (60.0 mg, 0.21 mmol),(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride(58.8 mg, 0.25 mmol), HATU (119.7 mg, 0.315 mmol) and DIPEA (135.5 mg,1.05 mmol) in DMF (5 mL) was stirred at RT for 16 h. The mixture wasconcentrated and purified by Prep-HPLC to giveN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((1,2,3-trimethyl-1H-indol-5-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(30.0 mg, yield: 31%) as a white solid. ESI-MS [M+H]⁺: 466.1. Purity:99.4% (214 nm), 98.6% (254 nm). ¹H NMR (400 MHz, DMSO-d₆) δ 8.66 (t,J=5.4 Hz, 1H), 8.54 (s, 1H), 8.43 (s, 1H), 8.20 (d, J=7.4 Hz, 1H), 7.47(s, 1H), 7.32 (d, J=8.4 Hz, 1H), 7.07 (dd, J=8.4, 1.5 Hz, 1H), 6.80-6.68(m, 1H), 5.65 (s, 2H), 4.68 (d, J=5.5 Hz, 2H), 3.61 (s, 3H), 2.31 (s,3H), 2.17 (s, 3H).

Example 270

Synthesis of Methyl1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-4-formyl-1H-pyrrole-2-carboxylate

A mixture of methyl 4-formyl-1H-pyrrole-2-carboxylate (0.2 g, 1.3 mmol)and 2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine (0.14 g, 1.7mmol) in DMF (5 mL) was stirred at 25° C. for 3 h. Water (30 mL) wasadded to the reaction, and extracted with EtOAc (20 mL×3). The combinedorganic layers was washed with brine, dried over Na₂SO₄, concentrated togive the crude, which was purified by silica gel chromatography(PE/EA=1/1) to give methyl1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-4-formyl-1H-pyrrole-2-carboxylate(251 mg, yield: 59%) as a pale solid. ESI-MS [M+H]⁺: 324.0.

Synthesis of1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-5-(methoxycarbonyl)-1H-pyrrole-3-carboxylicAcid

A solution of methyl1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-4-formyl-1H-pyrrole-2-carboxylate(0.2 g, 0.62 mmol) and KMnO₄ (0.15 g, 0.93 mmol) in THF (10 mL) and H₂O(10 mL). was stirred at 25° C. for 5 h. The reaction mixture wasfiltered and the filtrate was concentrated to give the crude, which waspurified by silica gel chromatography (DCM/MeOH=15/1) to give1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-5-(methoxycarbonyl)-1H-pyrrole-3-carboxylicacid (0.2 g, yield: 95.6%) as a white solid. ESI-MS [M+H]⁺: 340.1.

Synthesis of Methyl4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrrole-2-carboxylate(I-270a)

To a solution of1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-5-(methoxycarbonyl)-1H-pyrrole-3-carboxylicacid (0.2 g, 0.6 mmol) was added(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride(0.2 g, 0.9 mmol), HOBT (0.86 g, 0.72 mmol), EDCI (0.14 g, 0.72 mmol)and DIPEA (0.22 g, 1.8 mmol) in DMF (10 mL). The mixture was stirred at25° C. for 16 h. The solvent was removed by vacuo to give the crude,which was purified by Prep-HPLC to give methyl4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrrole-2-carboxylate(100 mg, yield: 33.3%) as a white solid. ESI-MS [M+H]⁺: 521.1. Purity:96.18% (214 nm), 96.94 (254 nm). ¹H NMR (400 MHz, DMSO-d₆) δ 8.44 (d,J=2.4 Hz, 1H), 8.40 (t, J=5.2 Hz, 1H), 8.30 (s, 1H), 8.20 (t, J=6.0 Hz,1H), 7.72 (d, J=1.9 Hz, 1H), 7.56 (s, 1H), 7.37 (t, J=5.7 Hz, 2H), 6.98(dd, J=9.4, 1.8 Hz, 1H), 6.76 (dd, J=7.2, 6.6 Hz, 1H), 5.59 (s, 2H),4.62 (t, J=3.5 Hz, 2H), 3.73 (s, 3H), 1.95-1.84 (m, 1H), 0.94-0.85 (m,2H), 0.69-0.61 (m, 2H).

Synthesis of4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrrole-2-carboxylicacid (I-270b)

To a solution of methyl4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrrole-2-carboxylate(60 mg, 0.12 mmol was added LiOH (0.02 g, 0.6 mmol) in THF (5 mL) andH₂O (5 mL). The mixture was stirred for 4 h at 25° C. The reaction wasconcentrated to remove the THF. The pH of the residue was acidified withHCl (1N) and white solid was precipitated. The mixture was filtered anddried to give4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrrole-2-carboxylicacid (46 mg, yield: 75%) as a white solid. ESI-MS [M+H]⁺: 507.1. Purity:97.86% (214 nm), 98.12% (254 nm). ¹H NMR (400 MHz, DMSO-d₆) δ 8.49 (s,1H), 8.45 (d, J=2.4 Hz, 1H), 8.40 (t, J=5.2 Hz, 1H), 8.21 (d, J=7.4 Hz,1H), 7.79-7.68 (m, 2H), 7.59 (d, J=9.4 Hz, 1H), 7.35-7.33 (m, 2H),6.82-6.72 (m, 1H), 5.70 (s, 2H), 4.63 (d, J=5.2 Hz, 2H), 2.05-1.90 (m,1H), 1.03-0.90 (m, 2H), 0.76-0.64 (m, 2H).

Example 271

Synthesis ofN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-imidazole-4-carboxamide(I-271)

A mixture of4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-imidazole-2-carboxylicacid (10 mg, 0.02 mmol) in DMSO (1 mL) was stirred at RT for 48 h. Water(10 mL) was added and the mixture was extracted with EtOAc (10 mL×3).The combined organic layers were washed with brine and dried overNa₂SO₄. After concentrated, the residue was purified by Prep-TLC(MeOH/DCM=10/1) to giveN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-imidazole-4-carboxamide(6.0 mg, yield: 66%) as a white solid. ESI-MS [M−H]⁻: 464.1. Purity:100% (214 nm), 99.7% (254 nm). ¹H NMR (400 MHz, DMSO-d₆) δ 8.45 (d,J=2.4 Hz, 1H), 8.33 (s, 1H), 8.20 (d, J=7.4 Hz, 1H), 8.01 (t, J=5.5 Hz,1H), 7.79 (d, J=1.2 Hz, 1H), 7.73 (s, 1H), 7.70 (d, J=1.2 Hz, 1H), 7.40(d, J=9.3 Hz, 1H), 7.00 (dd, J=9.4, 1.7 Hz, 1H), 6.79-6.72 (m, 1H), 5.31(s, 2H), 4.67 (d, J=5.5 Hz, 2H), 1.99-1.88 (m, 1H), 0.94-0.89 (m, 2H),0.71-0.58 (m, 2H).

Example 272

Synthesis of(3-(((tert-butyldiphenylsilyl)oxy)methyl)oxetan-3-yl)methanol

To a solution of oxetane-3,3-diyldimethanol (2.36 g, 20 mmol) in THF(120 mL) was added NaH (800 mg, 60% suspension in paraffin oil, 20 mmol)slowly at 0° C. The mixture was stirred at 0° C. for 30 min. Then asolution of TBDPSCl (5.48 g, 20 mmol) in THF (20 mL) was added to thereaction. The reaction was stirred at RT for 1 h. H₂O (150 mL) was addedand the mixture was extracted with EtOAc (150 mL×3). The combinedorganic layers were washed with brine, dried over Na₂SO₄, andconcentrated in vacuo to give(3-(((tert-butyldiphenylsilyl)oxy)methyl)oxetan-3-yl)methanol as ayellow oil, which was used in next step without further purification(6.5 g crude). ESI-MS [M+H]⁺: 357.1.

Synthesis of3-(((tert-butyldiphenylsilyl)oxy)methyl)oxetane-3-carbaldehyde

To a solution of oxalyl chloride (3.45 g, 28 mmol) in DCM (100 mL) wasadded DMSO (2.2 g, 28 mmol, solution in 10 mL DCM) slowly at −78° C. Thereaction was stirred for 30 min. Then a solution of(3-(((tert-butyldiphenylsilyl)oxy)methyl)oxetan-3-yl)methanol (6.5 gcrude from previous step) was added. The resulting reaction was stirredat −78° C. for 2 h. DIPEA (9.6 mL, 54 mmol) was added thereto. Afterstirring at −78° C. for 30 min, the reaction was quenched with aqueoussaturated NH₄Cl (100 mL) and extracted with DCM (100 mL×3). The combinedorganic layers were washed with brine, dried over Na₂SO₄, andconcentrated in vacuo to give the crude product as a yellow oil whichwas used into next step without further purification (5.2 g crude).ESI-MS [M+H]⁺: 355.2.

Synthesis of (2-amino-5-cyclopropylpyridin-3-yl)(3-(((tertbutyldiphenylsilyl)oxy)methyl)oxetan-3-yl)methanol

To a solution of 3-bromo-5-cyclopropylpyridin-2-amine (1 g, 4.7 mmol) indry THF (75 mL) was added n-BuLi (5.9 mL, 2.4 M in hexanes, 14 mmol) at−78° C. slowly. After stirring at −78° C. for 30 min, a solution of3-(((tert-butyldiphenylsilyl)oxy)methyl)oxetane-3-carbaldehyde (5.2 gcrude from previous step) in 20 mL THF was added thereto. The reactionwas stirred at −78° C. for 1 h. The reaction was quenched with aqueoussaturated NH₄Cl (100 mL) and extracted with EtOAc (100 mL×3). Thecombined organic layers were washed with brine, dried over Na₂SO₄, andconcentrated in vacuo to give the crude product, which was purifiedsilica gel chromatography (PE/EtOAc=1/1) to give(2-amino-5-cyclopropylpyridin-3-yl)(3-(((tert-butyldiphenylsilyl)oxy)methyl)oxetan-3-yl)methanol(600 mg, 26% over 2 steps). ESI-MS [M+H]⁺: 489.1.

Synthesis of(3-(((tert-butyldiphenylsilyl)oxy)methyl)oxetan-3-yl)(2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)methanol

A solution of(2-amino-5-cyclopropylpyridin-3-yl)(3-(((tert-butyldiphenylsilyl)oxy)methyl)oxetan-3-yl)methanol(600 mg, 1.23 mmol) and 1,3-dichloropropan-2-one (465 mg, 3.69 mmol) inDMF (15 mL) was stirred at 90° C. for 3 h. The reaction was quenchedwith saturated aqueous NaHCO₃ (50 mL) and extracted with EtOAc (75mL×4). The combined organic layers were washed with brine, dried overNa₂SO₄, and concentrated in vacuo to give the crude product, which waspurified with silica gel chromatography (DCM/MeOH=10/1) to give(3-(((tert-butyldiphenylsilyl)oxy)methyl)oxetan-3-yl)(2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)methanolas yellow oil (350 mg, 50.8%). ESI-MS [M+H]⁺: 561.2.

Synthesis of(2-(azidomethyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)(3-(((tert-butyldiphenylsilyl)oxy)methyl)oxetan-3-yl)methanol

A mixture of(3-(((tert-butyldiphenylsilyl)oxy)methyl)oxetan-3-yl)(2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)methanol(350 mg, 0.625 mmol) and NaN₃ (81 mg, 1.25 mmol) in DMF (5 mL) wasstirred at RT for 14 h. H₂O (50 mL) was added to the reaction, and themixture was extracted with EtOAc (50 mL×3). The combined organic layerswere washed with brine, dried over Na₂SO₄, and concentrated in vacuo togive the crude as a yellow oil which was used in the next step withoutfurther purification (360 mg crude). ESI-MS [M+H]⁺: 568.2.

Synthesis of benzyl1-((8-((3-(((tert-butyldiphenylsilyl)oxy)methyl)oxetan-3-yl)(hydroxy)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate

To a solution of(2-(azidomethyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)(3-(((tert-butyldiphenylsilyl)oxy)methyl)oxetan-3-yl)methanol(360 mg crude) and benzyl propiolate (120 mg, 0.75 mmol) in t-BuOH/H₂O(5 mL/5 mL) was added CuSO₄ (20 mg, 0.125 mmol) and sodium ascorbate (25mg, 0.125 mmol). The resulting mixture was stirred at RT for 3 h. H₂O(30 mL) was added to the reaction, and the mixture was extracted withEtOAc (50 mL×3). The combined organic layers were washed with brine,dried over Na₂SO₄, and concentrated in vacuo to give the crude productwhich was purified with Prep-TLC (DCM/MeOH=15/1) to give benzyl1-((8-((3-(((tert-butyldiphenylsilyl)oxy)methyl)oxetan-3-yl)(hydroxy)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(400 mg, 88% over 2 steps). ESI-MS [M+H]⁺: 728.2.

Synthesis of benzyl1-((6-cyclopropyl-8-(hydroxy(3-(hydroxymethyl)oxetan-3-yl)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate

To a solution benzyl1-((8-((3-(((tert-butyldiphenylsilyl)oxy)methyl)oxetan-3-yl)(hydroxy)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(200 mg, 0.275 mmol) in THF was added TBAF (0.275 mL, 1 M solution inTHF, 0.275 mmol). The resulting reaction was stirred at RT for 3 h. H₂O(30 mL) was added to the reaction, and the mixture was extracted withEtOAc (30 mL×3). The combined organic layers were washed with brine,dried over Na₂SO₄, and concentrated in vacuo to give the crude productwhich was purified by Prep-TLC (DCM/MeOH=10/1) to give benzyl1-((6-cyclopropyl-8-(hydroxy(3-(hydroxymethyl)oxetan-3-yl)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylateas a yellow solid (81 mg, 60%). ESI-MS [M+H]⁺: 490.2.

Synthesis of1-((6-cyclopropyl-8-(hydroxy(3-(hydroxymethyl)oxetan-3-yl)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicAcid

A mixture of benzyl1-((6-cyclopropyl-8-(hydroxy(3-(hydroxymethyl)oxetan-3-yl)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(81 mg, 0.165 mmol) and Pd/C (10 mg) in MeOH (5 mL) was stirred at RTunder H₂ atmosphere for 2 h. The reaction mixture was filtered and thefilter cake was washed with MeOH (50 mL). The filtrate was concentratedin vacuo to give1-((6-cyclopropyl-8-(hydroxy(3-(hydroxymethyl)oxetan-3-yl)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (65 mg, 98%) which was used in the next step directly. ESI-MS[M+H]⁺: 400.2.

Synthesis ofN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(hydroxy(3-(hydroxymethyl)oxetan-3-yl)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide

To a solution of1-((6-cyclopropyl-8-(hydroxy(3-(hydroxymethyl)oxetan-3-yl)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (65 mg, 0.163 mmol),(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride(50 mg, 0.211 mmol), HOBt (44 mg, 0.326 mmol) and EDCI (63 mg, 0.326mmol) in DMF (5 mL) was added DIPEA (65 mg, 0.5 mmol). The resultingreaction was stirred at RT for 16 h. H₂O (25 mL) was added to thereaction, and the mixture was extracted with EtOAc (40 mL×4). Thecombined organic layers were washed with brine, dried over Na₂SO₄, andconcentrated in vacuo to give the crude product which was purified byPrep-TLC (DCM/MeOH=10/1) to giveN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(hydroxy(3-(hydroxymethyl)oxetan-3-yl)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamideas a white solid (20 mg, 21%). ESI-MS [M+H]⁺: 581.2. Purity: 97.0% (214nm), 98.0% (254 nm). ¹H NMR (400 MHz, DMSO): δ 8.81 (t, J=5.4 Hz, 1H),8.70 (s, 1H), 8.58 (s, 1H), 8.49-8.40 (m, 2H), 8.29 (s, 1H), 8.21 (d,J=7.4 Hz, 1H), 7.60 (s, 1H), 7.14 (s, 1H), 6.76 (t, J=6.9 Hz, 1H), 6.14(s, 2H), 5.73 (s, 1H), 5.04 (s, 1H), 4.70 (d, J=5.5 Hz, 2H), 4.29 (d,J=13.0 Hz, 1H), 4.17 (d, J=13.0 Hz, 1H), 3.54 (d, J=11.4 Hz, 1H),3.45-3.25 (m, 3H), 2.15-2.08 (m, 1H), 1.13-1.00 (m, 2H), 0.83-0.70 (m,2H).

Example 273

Synthesis of 3-bromoquinoline-6-carboxylic Acid

A mixture of quinoline-6-carboxylic acid (5 g, 28.9 mmol), pyridine(4.57 g, 57.8 mmol) and Br₂ (5.5 g, 34.7 mmol) in CCl₄ (100 mL) wasstirred at 70° C. for 4 h. The reaction was cooled to RT, quenched withsaturated NaHCO₃ (150 mL), and extracted with MeOH/DCM (10/1, 100 mL×5).The combined organic layers were washed with brine, dried over Na₂SO₄and concentrated to give the crude product which was purified by flashcolumn chromatography (DCM/MeOH=15/1) to give3-bromoquinoline-6-carboxylic acid (6.2 g, yield: 85%) as a yellowsolid. ESI-MS [M+H]⁺: 253.1.

Synthesis of Ethyl 3-bromoquinoline-6-carboxylate

A mixture of 3-bromoquinoline-6-carboxylic acid (6.2 g, 24.7 mmol) inEtOH (100 mL) and H₂SO₄ (5 mL) was stirred at 90° C. for 14 h. Thereaction was then cooled to RT and concentrated. The residue wasquenched with saturated NaHCO₃ (150 mL) and extracted with EtOAc (100mL×3). The combined organic layers were washed with brine, dried overNa₂SO₄, and concentrated to give the crude product which was purified byflash column chromatography (PE/EtOAc=2/1) to afford ethyl3-bromoquinoline-6-carboxylate (3.6 g, yield: 53%) as an off-whitesolid. ESI-MS [M+H]⁺: 281.1.

Synthesis of Ethyl 3-cyclopropylquinoline-6-carboxylate

A mixture of 3-bromoquinoline-6-carboxylate (3.6 g, 12.9 mmol),cyclopropylboronic acid (1.66 g, 19.4 mmol), Pd(OAc)₂ (291 mg, 1.3mmol), PCy₃ (364 mg, 1.3 mmol) and K₃PO₄ (5.47 g, 25.8 mmol) indioxane/H₂O (50 mL/5 mL) was stirred at 100° C. for 12 h. The reactionmixture was diluted with water (150 mL) and extracted with EtOAc (100mL×3). The combined organic layers were washed with brine, dried overNa₂SO₄, and concentrated. The crude product was purified by flash columnchromatography (PE/EA=2/1) to afford ethyl3-cyclopropylquinoline-6-carboxylate (2.2 g, yield: 71%) as a brownsolid. ESI-MS [M+H]⁺: 242.1.

Synthesis of 3-cyclopropyl-6-(ethoxycarbonyl)quinoline 1-oxide

A mixture of ethyl 3-cyclopropylquinoline-6-carboxylate (2.0 g, 8.3mmol) and mCPBA (1.72 g, 10.0 mmol) in DCM (50 mL) was stirred at RT for14 h. The reaction mixture was quenched with saturated aqueous Na₂SO₃solution (50 mL) and extracted with DCM (70 mL×3). The combined organiclayers were washed with brine, dried over Na₂SO₄, and concentrated. Theresidue was purified by flash column chromatography (PE/EtOAc=2/1) toafford 3-cyclopropyl-6-(ethoxycarbonyl)quinoline 1-oxide (1.1 g, yield:43%) as an off-white solid. ESI-MS [M+H]⁺: 258.1.

Synthesis of 3-cyclopropyl-6-(ethoxycarbonyl)-8-iodoquinoline 1-oxide

A mixture of 3-cyclopropyl-6-(ethoxycarbonyl)quinoline 1-oxide (1.0 g,3.9 mmol), [RhCp*Cl₂]2 (247 mg, 0.4 mmol), NIS (963 mg, 4.28 mmol), andAgNTf₂ (155 mg, 0.4 mmol) in DCE (35 mL) was stirred at 50° C. for 14 h.The reaction mixture was filtered, and the filter cake washed with DCM(50 mL). The filtrate was concentrated to give the crude product whichwas purified by flash column chromatography (PE/EtOAc=1/2) to afford3-cyclopropyl-6-(ethoxycarbonyl)-8-iodoquinoline 1-oxide (1.2 g, yield:80%) as a yellow solid. ESI-MS [M+H]⁺: 384.1.

Synthesis of Ethyl 8-cyano-3-cyclopropylquinoline-6-carboxylate

A mixture of 3-cyclopropyl-6-(ethoxycarbonyl)-8-iodoquinoline 1-oxide(800 mg, 2.1 mmol), Zn(CN)₂ (366 mg, 3.1 mmol), Pd₂(dba)₃ (183 mg, 0.2mmol) and dppf (116 mg, 0.2 mmol) in DMF (20 mL) was stirred at 60° C.for 8 h. The reaction was diluted with water (100 mL) and extracted withEtOAc (80 mL×3). The combined organic layers were washed with brine,dried over Na₂SO₄, and concentrated to give the crude product which waspurified by flash column chromatography (PE/EtOAc=1/1) to afford ethyl8-cyano-3-cyclopropylquinoline-6-carboxylate (400 mg, yield: 72%) as ayellow solid. ESI-MS [M+H]⁺: 267.1.

Synthesis of 3-cyclopropyl-6-(hydroxymethyl)quinoline-8-carbonitrile

To a mixture of ethyl 8-cyano-3-cyclopropylquinoline-6-carboxylate (400mg, 1.5 mmol) in THF/MeOH (10 mL/5 mL) was added LiBH₄ (66 mg, 3.0mmol). The mixture was stirred at RT for 6 h. The reaction was dilutedwith water (50 mL) and extracted with DCM/MeOH (10/1, 50 mL×3). Thecombined organic layers were washed with brine, dried over Na₂SO₄ andconcentrated. The residue was purified by flash column chromatography(PE/EtOAc=1/3) to afford3-cyclopropyl-6-(hydroxymethyl)quinoline-8-carbonitrile (240 mg, yield:71%) as a yellow oil. ESI-MS [M+H]⁺: 225.1.

Synthesis of 6-(azidomethyl)-3-cyclopropylquinoline-8-carbonitrile

To a mixture of 3-cyclopropyl-6-(hydroxymethyl)quinoline-8-carbonitrile(240 mg, 1.07 mmol) and DPPA (880 mg, 3.2 mmol) in toluene (10 mL) wasadded DBU (486 mg, 3.2 mmol) at 0° C. The reaction mixture was stirredat RT for 12 h. The reaction was diluted with water (30 mL) andextracted with EtOAc (50 mL×3). The combined organic layers were washedwith brine, dried over Na₂SO₄ and concentrated to give the crude productwhich was purified by flash column chromatography (PE/EtOAc=2/1) toafford 6-(azidomethyl)-3-cyclopropylquinoline-8-carbonitrile (100 mg,yield: 37%) as brown oil. ESI-MS [M+H]⁺: 250.1.

Synthesis of tert-butyl1-((8-cyano-3-cyclopropylquinolin-6-yl)methyl)-1H-1,2,3-triazole-4-carboxylate

A mixture of 6-(azidomethyl)-3-cyclopropylquinoline-8-carbonitrile (100mg, 0.40 mmol), tert-butyl propiolate (76 mg, 0.60 mmol), CuSO₄ 5H₂O (20mg, 0.08 mmol) and sodium ascorbate (16 mg, 0.08 mmol) in t-BuOH/H₂O (5mL/1 mL) was stirred at RT for 3 h. The reaction was diluted with water(30 mL) and extracted with DCM/MeOH (10/1, 30 mL×3). The combinedorganic layers were washed with brine, dried over Na₂SO₄, andconcentrated. The residue was purified by flash column chromatography(DCM/MeOH=15/1) to afford tert-butyl1-((8-cyano-3-cyclopropylquinolin-6-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(110 mg, yield: 73%) as a brown oil. ESI-MS [M+H]⁺: 376.1.

Synthesis of1-((S-cyano-3-cyclopropylquinolin-6-yl)methyl)-1H-1,2,3-triazole-4-carboxylicAcid

A mixture of tert-butyl1-((8-cyano-3-cyclopropylquinolin-6-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(100 mg, 0.27 mmol) in HCl (5 mL, 4 M solution in dioxane, 20 mmol) wasstirred at RT for 3 h. The mixture was concentrated to afford1-((8-cyano-3-cyclopropylquinolin-6-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (110 mg, crude) as a brown oil which was used in the next stepwithout further purification. ESI-MS [M+H]⁺: 320.1.

Synthesis ofN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((8-cyano-3-cyclopropylquinolin-6-yl)methyl)-1H-1,2,3-triazole-4-carboxamide

A mixture of1-((8-cyano-3-cyclopropylquinolin-6-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (110 mg, 0.27 mmol crude),(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride(97 mg, 0.41 mmol), HOBT (55 mg, 0.41 mmol), EDCI (78 mg, 0.41 mmol) andDIEA (105 mg, 0.81 mmol) in DMF (3 mL) was stirred at RT for 14 h. Thereaction mixture was diluted with water (50 mL) and extracted with EtOAc(30 mL×3). The combined organic layers were washed with brine, driedover Na₂SO₄, and concentrated. The residue was purified by Prep-TLC(DCM/MeOH=10/1) to affordN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((8-cyano-3-cyclopropylquinolin-6-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(67 mg, yield: 50%) as white solid. ESI-MS [M+H]⁺: 501.1. Purity: 97.79%(214 nm), 95.14% (254 nm). ¹H NMR (400 MHz, DMSO): δ 8.96 (s, 1H),8.74-8.72 (m, 2H), 8.32 (s, 1H), 8.21 (d, J=8.0 Hz, 1H), 8.13 (s, 1H),8.05 (s, 1H), 6.79 (s, 1H), 5.89 (s, 2H), 4.71 (s, 2H), 2.20-2.18 (m,1H), 1.14-1.12 (m, 2H), 0.94-0.91 (m, 2H).

Example 274

Synthesis of Ethyl 6-cyclopropyl-1H-indole-2-carboxylate

A mixture of ethyl 6-bromo-1H-indole-2-carboxylate (3.5 g, 13.05 mmol),cyclopropylboronic acid (2.24 g, 26.11 mmol), Pd(OAc)₂ (146 mg, 0.653mmol), SPhos (537 mg, 1.31 mmol) and K₃PO₄ (8.30 g, 39.15 mmol) intoluene (60 mL) and water (10 mL) was stirred at 90° C. for 16 h underN₂. The reaction mixture was filtered and the filter cake rinsed withEtOAc (200 mL). The combined filtrate was washed with water (100 mL×1)and brine (100 mL×1), dried over Na₂SO₄, concentrated and purified bysilica gel chromatography (EA/PE=1/3) to give ethyl6-cyclopropyl-1H-indole-2-carboxylate (2.9 g, yield: 97%) as a yellowsolid. ESI-MS [M+H]⁺: 230.1.

Synthesis of Ethyl 3-bromo-6-cyclopropyl-1H-indole-2-carboxylate

To a stirred solution of ethyl 6-cyclopropyl-1H-indole-2-carboxylate(2.9 g, 12.66 mmol) in THF (60 mL) was added NBS (2.79 g, 15.7 mmol) inportions at 0° C. The mixture was stirred at 25° C. for 2 h. Thereaction mixture was diluted in EtOAc (100 mL), washed with saturatedaqueous NaHCO₃ (100 mL) and brine (100 mL), dried over Na₂SO₄, andconcentrated in vacuo to give ethyl3-bromo-6-cyclopropyl-1H-indole-2-carboxylate (4.0 g, crude) as a yellowsolid. ESI-MS [M+Na]⁺: 330.0.

Synthesis of Ethyl3-bromo-6-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-2-carboxylate

To a stirred solution of NaH (564 mg, 60% suspension in paraffin oil,14.1 mmol) in THF (20 mL) was added dropwise the solution of ethyl3-bromo-6-cyclopropyl-1H-indole-2-carboxylate (2.9 g, 9.45 mmol) in THF(30 mL) at 0° C. The mixture was stirred at 0° C. for 10 min and SEMCl(2.04 g, 12.24 mmol) was added dropwise at 0° C. The mixture was stirredat 25° C. for 2 h. The reaction mixture was quenched with water (80 mL)and extracted with EtOAc (80 mL×2). The combined organics were washedwith brine (150 mL), dried over Na₂SO₄, concentrated in vacuo to giveethyl3-bromo-6-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-2-carboxylate(4.1 g, crude) as a light brown syrup. ESI-MS [M+Na]⁺: 460.1.

Synthesis of(3-bromo-6-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-2-yl)methanol

To a stirred solution of ethyl3-bromo-6-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-2-carboxylate(750 mg, 1.71 mmol) in DCM (30 mL) was added dropwise DIBAL-H (6.8 mL,6.8 mmol) at 0° C. The mixture was stirred at 0° C. for 1 h. Thereaction mixture was quenched with saturated aqueous NH₄Cl and extractedwith DCM (30 mL×3). The combined organics were washed with brine (90mL), dried over Na₂SO₄, and purified by silica gel chromatography(EA/PE=1/2) to give(3-bromo-6-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-2-yl)methanol(450 mg, yield: 66%) as a colorless liquid. ESI-MS [M+Na]⁺: 418.0.

Synthesis of2-(azidomethyl)-3-bromo-6-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole

To a stirred solution of(3-bromo-6-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-2-yl)methanol(400 mg, 1.01 mmol) and DPPA (834 mg, 3.03 mmol) in DCM (15 mL) wasadded dropwise the solution of DBU (153 mg, 1.01 mmol) in DCM (1 mL) at0° C. The mixture was stirred at 25° C. for 16 h. The reaction mixturewas concentrated and purified by silica gel chromatography (EA/PE=1/5)to give2-(azidomethyl)-3-bromo-6-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole(270 mg, yield: 64%) as a yellow liquid. ESI-MS [M+H]⁺: 421.0.

Synthesis of tert-butyl1-((3-bromo-6-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate

A mixture of2-(azidomethyl)-3-bromo-6-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole(270 mg, 0.64 mmol), ethyl isobutyrate (105 mg, 0.832 mmol), CuSO₄ (51mg, 0.32 mmol), and sodium ascorbate (63 mg, 0.32 mmol) in t-BuOH (5 mL)and water (5 mL) was stirred at 25° C. for 16 h. The reaction wasconcentrated to remove t-BuOH, then diluted with water (30 mL) andextracted with DCM (30 mL×2). The combined organics were washed withbrine (60 mL×1), dried over Na₂SO₄, concentrated and purified by silicagel chromatography (EA/PE=1/1) to afford tert-butyl1-((3-bromo-6-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(270 mg, yield: 77%) as a yellow solid. ESI-MS [M+Na]⁺: 569.1.

Synthesis of Methyl2-((4-(tert-butoxycarbonyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-3-carboxylate

A mixture of tert-butyl1-((3-bromo-6-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(270 mg, 0.493 mmol), Pd(dppf)Cl₂ (36 mg, 0.049 mmol) and Et₃N (748 mg,7.40 mmol) in MeOH (25 mL) was stirred at 75° C. for 40 h under CO(balloon). The reaction mixture was concentrated and purified by silicagel chromatography (EA/PE=1/5) to afford methyl2-((4-(tert-butoxycarbonyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-3-carboxylate(70 mg, yield: 27%) as a yellow solid. ESI-MS [M+Na]⁺: 549.2.

Synthesis of1-((6-cyclopropyl-1-(hydroxymethyl)-3-(methoxycarbonyl)-1H-indol-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicAcid

A mixture of methyl2-((4-(tert-butoxycarbonyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-3-carboxylate(50 mg, 0.095 mmol) and TFA (0.3 mL) in DCM (2 mL) was stirred at 25° C.for 16 h. The reaction mixture was concentrated in vacuo to give1-((6-cyclopropyl-1-(hydroxymethyl)-3-(methoxycarbonyl)-1H-indol-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (35 mg, 100%) as a purple solid. ESI-MS [M+Na]⁺: 393.1.

Synthesis of Methyl2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropyl-1H-indole-3-carboxylate

The mixture of1-((6-cyclopropyl-1-(hydroxymethyl)-3-(methoxycarbonyl)-1H-indol-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (35 mg, 0.095 mmol),(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride(25 mg, 0.105 mmol), EDCI (36 mg, 0.19 mmol), HOBT (26 mg, 0.19 mmol),and DIPEA (123 mg, 0.95 mmol) in DMF (2 mL) was stirred at 25° C. for 16h. The reaction mixture was poured into water (20 mL) and theprecipitate was collected, dried in vacuo and purified by silica gelchromatography (EA/MeOH=40/1) to give methyl2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropyl-1H-indole-3-carboxylate(14 mg, yield: 28%) as a white solid. ESI-MS [M+H]⁺: 522.1. Purity:96.95% (214 nm), 96.72% (254 nm). ¹H NMR (400 MHz, DMSO): δ 12.06 (s,1H), 8.73 (t, J=5.5 Hz, 1H), 8.53 (s, 1H), 8.43 (d, J=2.4 Hz, 1H), 8.20(d, J=7.4 Hz, 1H), 7.83 (d, J=8.3 Hz, 1H), 7.12 (s, 1H), 6.94 (dd,J=8.4, 1.5 Hz, 1H), 6.78-6.73 (m, 1H), 6.06 (s, 2H), 4.69 (d, J=5.5 Hz,2H), 3.84 (s, 3H), 2.05-1.96 (m, 1H), 0.98-0.91 (m, 2H), 0.69-0.62 (m,2H).

Synthesis of2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropyl-1H-indole-3-carboxylicAcid

To the solution of methyl2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropyl-1H-indole-3-carboxylate(50 mg, 0.096 mmol) in 1,4-dioxane (6 mL) and H₂O (3 mL) was added NaOH(300 mg, 7.5 mmol) and the mixture was stirred at 60° C. for 40 h. Thereaction mixture was diluted in water (20 mL), 1,4-dioxane was removedin vacuo, and the mixture was acidified to pH 4-5 by addition of HCl (2M). The precipitate was collected and purified by Prep-HPLC to give2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropyl-1H-indole-3-carboxylicacid (3 mg, yield: 6%) as a white solid. ESI-MS [M+H]⁺: 508.1. Purity:94.86% (214 nm), 92.71% (254 nm). ¹H NMR (400 MHz, DMSO): δ 11.92 (s,1H), 8.73 (t, J=5.5 Hz, 1H), 8.54-8.40 (m, 2H), 8.20 (d, J=7.4 Hz, 1H),7.87 (d, J=8.3 Hz, 1H), 7.10 (s, 1H), 6.93-6.86 (m, 1H), 6.81-6.71 (m,1H), 6.07 (s, 2H), 4.69 (d, J=5.5 Hz, 2H), 2.05-1.96 (m, 1H), 0.95-0.91(m, 2H), 0.67-0.63 (m, 2H).

Example 275

Synthesis of6-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-3-cyclopropylquinoline-s-carboxamide

A mixture ofN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((8-cyano-3-cyclopropylquinolin-6-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(50 mg, 0.1 mmol) in concentrated H₂SO₄ (2 mL) was heated to 80° C. bymicrowave for 30 min. The reaction mixture was adjusted to pH 7-8 withsaturated aqueous NaHCO₃. The aqueous phase was extracted with EtOAc (30mL×3). The combined organic layers were washed with brine, dried overNa₂SO₄, and concentrated in vacuo to give the crude product which waspurified by Prep-TLC (DCM/MeOH=8/1) to give6-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-3-cyclopropylquinoline-8-carboxamide.(8 mg, 15.4%). ESI-MS [M+H]⁺: 518.7. Purity: 93.90% (214 nm) 96.01 (254nm). ¹H NMR (400 MHz, DMSO): δ 10.06 (d, J=4.4 Hz, 1H), 9.14 (d, J=2.4Hz, 1H), 8.75 (t, J=6.0 Hz, 1H), 8.73 (s, 1H), 8.44 (s, 1H), 8.41 (d,J=2.0 Hz, 1H), 8.20 (d, J=7.6, 1H), 7.99 (s, 1H), 7.97 (s, 1H), 7.33 (s,1H), 5.91 (s, 2H), 4.71 (d, J=5.6 Hz, 2H), 2.35-2.31 (m, 1H), 0.81-0.88(m, 4H).

Synthesis of Methyl1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrrole-3-carboxylate

A solution of 2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine (207mg, 1.0 mmol), methyl 1H-pyrrole-3-carboxylate (250 mg, 2.0 mmol) andCs₂CO₃ (652 mg, 2.0 mmol) in DMF (6 mL) was stirred at 60° C. overnight.The mixture was diluted with water (60 mL) and extracted by EtOAc (50mL×3). The combined organic layers were washed with brine, dried overNa₂SO₄ and concentrated. The crude product was purified by Prep-TLC(DCM/MeOH=20/1) to afford methyl1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrrole-3-carboxylateas a white solid (72 mg, 24%). ESI-MS [M+H]⁺: 296.1.

Synthesis of1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrrole-3-carboxylicAcid

A solution of methyl1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrrole-3-carboxylate(72 mg, 0.24 mmol) and LiOH*H₂O (20 mg, 0.48 mmol) in THF (3 mL)/MeOH (3mL)/H₂O (1.5 mL) was stirred at 60° C. for 4 h. The mixture wasconcentrated to give the product (88 mg, crude), which was used into thenext reaction without further purification. ESI-MS [M+H]⁺: 282.1.

Synthesis ofN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrrole-3-carboxamide

A solution of crude1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrrole-3-carboxylicacid (45 mg, 0.160 mmol, crude),(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride(42 mg, 0.176 mmol), HOBT (43 mg, 0.320 mmol), EDCI (62 mg, 0.320 mmol)and DIPEA (104 mg, 0.8 mmol) in DMF (1 mL) was stirred at 50° C.overnight. The mixture was diluted with water (10 mL) and extracted byEtOAc (50 mL×3). The combined organic layers were concentrated andpurified by Prep-TLC (DCM/MeOH=7/1) to affordN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrrole-3-carboxamideas a white solid (3.3 mg, 4.5%). MS [M+H]⁺: 463.1. Purity: 94.04% (214nm), 94.01% (254 nm). ¹H NMR (400 MHz, DMSO): δ 8.43 (d, J=1.8 Hz, 1H),8.32 (s, 1H), 8.19 (d, J=7.4 Hz, 1H), 8.06 (t, J=5.1 Hz, 1H), 7.64 (s,1H), 7.39-7.37 (m, 2H), 6.98 (d, J=9.3 Hz, 1H), 6.80-6.73 (m, 2H), 6.44(s, 1H), 5.14 (s, 2H), 4.60 (d, J=5.2 Hz, 2H), 1.94-1.87 (m, 1H),0.93-0.88 (m, 2H), 0.67-0.64 (m, 2H).

Example 277

Synthesis of 7-chloro-6-fluoroimidazo[1,5-a]pyridine-1-carbaldehyde

7-chloro-6-fluoroimidazo[1,5-a]pyridine (358 mg, 2.09 mmol) wasdissolved in dry N,N-dimethylformamide (1.8 mL) and the resultingsolution was cooled in an ice-bath. Phosphorous oxychloride (196 μL,2.09 mmol) was added and the resulting suspension heated to 110° C. for2 h. The mixture was cooled to RT and mixed with ethyl acetate (10 mL)and saturated aqueous sodium bicarbonate (10 mL). Both layers werecombined and evaporated to dryness. The resulting solid was mixed withacetone and the insoluble salts filtered off. The filtrate was purifiedby silica gel chromatography (heptane/EA=80/20 to 30/70) to obtain7-chloro-6-fluoroimidazo[1,5-a]pyridine-1-carbaldehyde (182 mg, 44%) asa yellow solid. UPLC [M+H]⁺: 199/201.

Synthesis ofN-((7-chloro-6-fluoroimidazo[1,5-a]pyridin-1-yl)methylene)-2-methylpropane-2-sulfinamide

To a solution of 7-chloro-6-fluoroimidazo[1,5-a]pyridine-1-carbaldehyde(206 mg, 1.04 mmol) and 2-methyl-2-propanesulfinamide (132 mg, 1.09mmol) in anhydrous tetrahydrofuran (8 mL) was added titanium (IV)ethoxide (544 μL, 2.59 mmol). The resulting solution was heated underreflux overnight (65° C., 18 h). The solvent had evaporated overnight toleave an orange gum, which was dissolved in acetone, absorbed ontosilica gel and purified by silica gel chromatography (EA/MeOH=9/1) toaffordN-((7-chloro-6-fluoroimidazo[1,5-a]pyridin-1-yl)methylene)-2-methylpropane-2-sulfinamide(292 mg, 93%) as a bright yellow solid. UPLC [M+H]⁺: 302/303.

Synthesis ofN-((7-chloro-6-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-2-methylpropane-2-sulfinamide

To a solution ofN-((7-chloro-6-fluoroimidazo[1,5-a]pyridin-1-yl)methylene)-2-methylpropane-2-sulfinamide(292 mg, 0.968 mmol) in methanol (8 mL) was added sodium borohydride (92mg, 2.42 mmol) in small portions over 5 min. The resulting yellowsolution was stirred for 90 min at RT. More sodium borohydride (ca. 20mg, 0.53 mmol) was added and the mixture stirred for another 30 min.Water (2 mL) was added and the cloudy mixture poured into saturatedaqueous sodium bicarbonate (15 mL). The product was extracted into ethylacetate (3×15 mL). The combined organic solutions were washed withbrine, dried (MgSO₄), filtered and concentrated to dryness to obtainN-((7-chloro-6-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-2-methylpropane-2-sulfinamide(272 mg, 92%) as a light yellow solid. LCMS [M+H]⁺: 304/306,[M−^(t)BuSONH]⁺: 183/185.

Synthesis of (7-chloro-6-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine

To a suspension ofN-((7-chloro-6-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-2-methylpropane-2-sulfinamide(272 mg, 0.897 mmol) in 1,4-dioxane (6.8 mL) was added a solution ofhydrogen chloride in 1,4-dioxane (4 M, 2.2 mL, 8.8 mmol). The resultingsuspension was stirred for 90 min at RT. The reaction mixture wasconcentrated to dryness and repeatedly evaporated from methanol toobtain an off-white solid (272 mg). The solid was dissolved indimethylsulfoxide/15% aqueous ammonia=2:1 (ca. 3 mL) and applied to aBiotage SNAP ULTRA C₁₈ 30 g cartridge and eluted with a gradient ofwater/acetonitrile from 90/10 to 0:100 (each containing 0.1% (v/v)ammonia) to obtain(7-chloro-6-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine (154 mg, 86%)as a yellow solid. LCMS [M+H−NH₃]⁺: 183/185.

Synthesis ofN-((7-chloro-6-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide

To a solution of1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (42 mg, 0.15 mmol),(7-chloro-6-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine (35 mg, 0.15mmol), HOBT (30 mg, 0.226 mmol), and EDCI (43.4 mg, 0.226 mmol) in DMF(2 mL) was added DIPEA (78 mg, 0.6 mmol). The resulting mixture wasstirred at RT for 14 h. Water (20 mL) was added, and the mixture wasextracted with EtOAc (10 mL×3). The combined organic layers were washedwith brine, dried over Na₂SO₄, filtered and concentrated to give thecrude product which was purified by Prep-TLC (DCM/MeOH=10/1) to giveN-((7-chloro-6-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(42 mg, yield: 60%) as a white solid. ESI-MS [M+H]⁺: 465.1. Purity:99.01% (214 nm), 96.62% (254 nm). ¹H NMR (400 MHz, DMSO): δ 8.96 (t,J=5.9 Hz, 1H), 8.69 (dd, J=5.0, 0.5 Hz, 1H), 8.56 (s, 1H), 8.34 (s, 1H),8.29 (s, 1H), 8.08 (d, J=7.3 Hz, 1H), 7.82 (s, 1H), 7.40 (d, J=9.3 Hz,1H), 7.01 (dd, J=9.4, 1.8 Hz, 1H), 5.72 (s, 2H), 4.62 (d, J=5.9 Hz, 2H),1.96-1.89 (m, 1H), 0.94-0.89 (m, 2H), 0.74-0.57 (m, 2H).

Example 278

Synthesis ofN-(1-(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)ethyl)-1-(1-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)ethyl)-1H-1,2,3-triazole-4-carboxamide

To a mixture of1-(1-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)ethyl)-1H-1,2,3-triazole-4-carboxylicacid (60 mg, 0.2 mmol),1-(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)ethan-1-amine (52 mg,0.24 mmol), HOBT (54 mg, 0.4 mmol), EDCI (76 mg, 0.4 mmol) in DMF (5 mL)was added DIPEA (130 mg, 1 mmol). The mixture was stirred at 25° C. for16 h. Water (50 mL) was added, and the mixture was extracted with EtOAc(20 mL×3). The combined organic layers were washed with brine andconcentrated. The crude product was purified by Prep-TLC (DCM/MeOH=10/1)to giveN-(1-(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)ethyl)-1-(1-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)ethyl)-1H-1,2,3-triazole-4-carboxamide(23.5 mg, yield: 23.9%) as a yellow solid. ESI-MS [M+H]⁺: 493.1. Purity:100% (214 nm), 100 (254 nm). ¹H NMR (400 MHz, DMSO): δ 8.63 (d, J=3.2Hz, 1H), 8.48 (d, J=2.4 Hz, 1H), 8.39 (d, J=7.7 Hz, 1H), 8.32 (s, 1H),8.21 (d, J=7.4 Hz, 1H), 7.77 (d, J=1.8 Hz, 1H), 7.41 (d, J=9.4 Hz, 1H),7.01 (d, J=9.6 Hz, 1H), 6.79-6.74 (m, 1H), 6.15-6.10 (m, 1H), 5.57-5.50(m, 1H), 1.93-1.91 (m, 4H), 1.54 (d, J=6.8 Hz, 3H), 0.93-0.90 (m, 2H),0.67-0.66 (m, 2H).

Example 279

Synthesis of (2-amino-5-cyclopropylpyridin-3-yl)(oxetan-3-yl)methanol

To a solution of 3-bromo-5-cyclopropylpyridin-2-amine (500 mg, 2.35mmol) in dry THF (25 mL) was added n-BuLi (3.5 mL, 2.4 M solution inhexanes, 8.4 mmol) at −60° C. The resulting mixture was stirred at −60°C. for 30 min. Then a solution of oxetane-3-carbaldehyde (714 mg, 8.3mmol) in 3 mL THF was added slowly at −60° C. and stirred for another 30min. The reaction was quenched with water (10 mL) and concentrated invacuo to give the crude residue, which was purified by Prep-TLC(DCM/MeOH=6/1) to give(2-amino-5-cyclopropylpyridin-3-yl)(oxetan-3-yl)methanol as a yellow oil(310 mg, 60%). ESI-MS [M+H]⁺: 221.2.

Synthesis of(2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)(oxetan-3-yl)methanol

A mixture of (2-amino-5-cyclopropylpyridin-3-yl)(oxetan-3-yl)methanol(310 mg, 1.41 mmol) and 1,3-dichloropropan-2-one (533 mg, 4.23 mmol) inEtOH (25 mL) was stirred at 80° C. for 14 h. The reaction mixture wasadjusted to pH 8 using saturated aqueous NaHCO₃ and concentrated invacuo to give the crude residue, which was purified by Prep-TLC(DCM/MeOH=10/1) to give(2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)(oxetan-3-yl)methanolas a yellow oil (210 mg, 51%). ESI-MS [M+H]⁺: 293.2.

Synthesis of(2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)(oxetan-3-yl)methanol

To a solution of(2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)(oxetan-3-yl)methanol(210 mg, 0.72 mmol) in DMF (5 mL) was added NaN₃ (70 mg, 1.08 mmol). Theresulting mixture was stirred at RT for 3 h. The reaction wasconcentrated in vacuo to give the crude residue (280 mg, crude), whichwas used in next step without further purification. ESI-MS [M+H]⁺:300.2.

Synthesis of Ethyl1-((6-cyclopropyl-8-(hydroxy(oxetan-3-yl)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate

To a solution of(2-(azidomethyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)(oxetan-3-yl)methanol(210 mg, 0.7 mmol) in t-BuOH/H₂O (15 mL/15 mL) was added ethylpropiolate (89 mg, 0.91 mmol), CuSO₄ (45 mg, 0.28 mmol) and sodiumascorbate (54 mg, 0.28 mmol). The reaction was stirred at RT for 3 h.Water (15 mL) was added to the reaction, and the mixture was extractedwith DCM/MeOH (15/1, 30 mL×3). The combined organic layers were driedover Na₂SO₄ and concentrated in vacuo to give the crude residue, whichwas purified by Prep-TLC (DCM/MeOH=10/1) to give ethyl1-((6-cyclopropyl-8-(hydroxy(oxetan-3-yl)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylateas yellow solid. (210 mg, 75%). ESI-MS [M+H]⁺: 398.2.

Synthesis of1-((6-cyclopropyl-8-(hydroxy(oxetan-3-yl)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicAcid

To a solution of ethyl1-((6-cyclopropyl-8-(hydroxy(oxetan-3-yl)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(210 mg, 0.53 mmol) in THF/H₂O (8 mL/8 mL) was added LiOH.H₂O (65 mg,1.58 mmol). The reaction was stirred at RT for 2 h. The reaction mixturewas then adjusted to pH 5 using 1N HCl, and freeze-dried to give1-((6-cyclopropyl-8-(hydroxy(oxetan-3-yl)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (300 mg crude) which was used into next step without furtherpurification. ESI-MS [M+H]⁺: 370.1.

Synthesis ofN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(hydroxy(oxetan-3-yl)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide

To a solution of1-((6-cyclopropyl-8-(hydroxy(oxetan-3-yl)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (100 mg crude from previous step) in DMF (3 mL) was added(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride(54 mg, 0.23 mmol), HOBT (36.5 mg, 0.27 mmol), EDCI (52 mg, 0.27 mmol)and DIPEA (110 mg, 0.85 mmol). The resulting reaction was stirred at RTfor 12 h. The reaction was concentrated in vacuo to give the crudeproduct which was purified by Prep-HPLC to giveN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(hydroxy(oxetan-3-yl)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamideas a white solid (7 mg, 7.2% over 2 steps). ESI-MS [M+H]⁺: 551.1.Purity: 98.95% (214 nm), 100% (254 nm). ¹H NMR (400 MHz, DMSO): δ8.88-8.77 (m, 1H), 8.71-8.61 (m, 2H), 8.48-8.44 (m, 2H), 8.32 (d, J=5.1Hz, 1H), 8.21 (d, J=7.4 Hz, 1H), 7.65 (d, J=8.4 Hz, 1H), 6.76 (t, J=6.9Hz, 1H), 6.14 (d, J=7.7 Hz, 2H), 5.02 (s, 0.5H), 4.88 (d, J=8.9 Hz,0.5H), 4.70 (d, J=5.4 Hz, 2H), 4.56-4.52 (m, 1H), 4.11-4.06 (m, 0.5H),3.92-3.87 (m, 0.5H), 3.77-3.60 (m, 2H), 3.51-3.47 (m, 1H), 2.17-2.08 (m,1H), 1.11-1.06 (m, 2H), 0.85-0.75 (m, 2H).

Example 280

Synthesis ofN-(1-(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)ethyl)-2-methylpropane-2-sulfinamide

Methyl magnesium bromide (3.0 M in ethyl ether, 34 mL, 102.0 mmol) wasadded slowly to a solution ofN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methylene)-2-methylpropane-2-sulfinamide(12.0 g, 39.7 mmol) in tetrahydrofuran (100 mL) at −78° C. The resultingmixture was stirred for 0.5 h at −78° C. The reaction was quenched withsaturated aqueous NH₄Cl (100 mL), and extracted with dichloromethane(200 mL×3). The combined organic layers were washed with brine, driedover with Na₂SO₄, filtered, and concentrated. The residue was purifiedby silica gel column chromatography (petroleum ether/ethyl acetate=3/1)to affordN-(1-(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)ethyl)-2-methylpropane-2-sulfinamide(6.8 g, yield: 54%) as a yellow solid. ESI-MS [M+H]⁺: 318.1.

Synthesis of1-(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)ethan-1-aminehydrochloride

A mixture ofN-(1-(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)ethyl)-2-methylpropane-2-sulfinamide(6.8 g, 21.4 mmol) and hydrochloric acid in ethyl acetate (3 M, 30 mL)was stirred at RT for 1 h. The reaction mixture was filtered to give thecrude product, which was washed with dichloromethane and dried in vacuoto give 1-(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)ethanaminehydrochloride (5.3 g, 100%) as a white solid. ESI-MS [M-NH₂]⁺: 197.0.

Synthesis ofN-(1-(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)ethyl)-1-((6-cyclopropyl-8-(hydroxy(oxetan-3-yl)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide

To a solution of1-((6-cyclopropyl-8-(hydroxy(oxetan-3-yl)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (100 mg crude from previous step) in DMF (10 mL) was added1-(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)ethan-1-amine (49 mg,0.23 mmol), HOBT (36.5 mg, 0.27 mmol), EDCI (52 mg, 0.27 mmol) and DIPEA(110 mg, 0.85 mmol). The reaction mixture was stirred at RT for 12 h.The reaction was concentrated in vacuo to give the crude product whichwas purified by prep-HPLC to giveN-(1-(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)ethyl)-1-((6-cyclopropyl-8-(hydroxy(oxetan-3-yl)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamideas a white solid (17 mg, 17% for two steps). ESI-MS [M+H]⁺: 565.1.Purity: 98.75% (214 nm), 96.56% (254 nm). ¹H NMR (400 MHz, DMSO): δ 8.71(d, J=11.2 Hz, 1H), 8.63 (d, J=20.3 Hz, 1H), 8.55-8.43 (m, 3H), 8.32 (d,J=5.4 Hz, 1H), 8.21 (d, J=7.4 Hz, 1H), 7.65 (d, J=9.4 Hz, 1H), 6.77 (t,J=7.0 Hz, 1H), 6.16 (t, J=12.5 Hz, 2H), 5.57-5.50 (m, 1H), 5.03 (s,0.5H), 4.88 (d, J=8.8 Hz, 0.5H), 4.58-4.51 (m, 1H), 4.11-4.06 (m, 0.5H),3.92-3.87 (m, 0.5H), 3.77-3.60 (m, 2H), 3.51-3.47 (m, 1H), 2.16-2.08 (m,1H), 1.55 (d, J=6.8 Hz, 3H), 1.10-0.98 (m, 2H), 0.89-0.66 (m, 2H).

Example 281

Synthesis of Methyl 2-(N-methyl-N-phenylsulfamoyl)acetate

To a solution of N-methylaniline (1.07 g, 10 mmol) in DCM (30 mL) wasadded methyl 2-(chlorosulfonyl)acetate (860 mg, 5 mmol) at 0° C.dropwise. The resulting mixture was stirred at RT for 18 h, thenquenched with saturated aqueous NH₄Cl solution (50 mL) and extractedwith EtOAc (100 mL×3). The combined organic layers were washed withbrine, dried over Na₂SO₄, and concentrated in vacuo to give the crudeproduct which was purified by silica gel column (PE/EtOAc=2/1) to givethe methyl 2-(chlorosulfonyl)acetate as a white solid (850 mg, 70%).ESI-MS [M+H]⁺: 244.1.

Synthesis of1-((6-cyclopropyl-8-(2-methoxy-1-(N-methyl-N-phenylsulfamoyl)-2-oxoethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicAcid

To a solution of methyl 2-(N-methyl-N-phenylsulfamoyl) acetate (450 mg,1.85 mmol) in dry dioxane (25 mL) was added t-BuONa (442 mg, 4.6 mmol)at 0° C. The resulting mixture was stirred at RT for 5 min. Thentert-butyl1-((8-bromo-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(385 mg, 0.92 mmol), Pd(OAc)₂ (43 mg, 0.184 mmol), and t-Bu₃PH—BF₄ (107mg, 0.368 mmol) were added. The resulting mixture was stirred at 90° C.for 30 min. The reaction was poured into HCl (0.5M, 15 mL) and extractedwith DCM/MeOH (15/1, 50 mL×3). The combined organic layers were washedwith brine, dried over Na₂SO₄, and concentrated in vacuo to give thecrude product, which was purified with silica gel column (10/1) to give1-((6-cyclopropyl-8-(2-methoxy-1-(N-methyl-N-phenylsulfamoyl)-2-oxoethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid as a yellow solid (200 mg, 41%). ESI-MS [M+H]⁺: 525.2.

Synthesis of1-((6-cyclopropyl-8-(2-methoxy-2-oxo-1-(N-(2,2,2-trifluoroethyl)sulfamoyl)ethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic Acid

A solution of1-((6-cyclopropyl-8-(2-methoxy-1-(N-methyl-N-phenylsulfamoyl)-2-oxoethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (200 mg, 0.38 mmol) and 2,2,2-trifluoroethan-1-amine (376 mg, 3.8mmol) in NMP (5 mL) was stirred at 100° C. for 12 h. The reaction wasconcentrated in vacuo to give the crude product which was used in thenext step without further purification. (210 mg crude). ESI-MS [M+H]⁺:517.2.

Synthesis of1-((6-cyclopropyl-8-((N-(2,2,2-trifluoroethyl)sulfamoyl)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicAcid

To a solution of1-((6-cyclopropyl-8-(2-methoxy-2-oxo-1-(N-(2,2,2-trifluoroethyl)sulfamoyl)ethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (210 mg crude from previous step) in MeOH (10 mL) was added NaOH(76 mg, 1.9 mmol) in water (2 mL). The resulting mixture was stirred atRT for 1 h. The reaction was concentrated and the residue was adjustedto about pH 5 using 1N hydrochloric acid. The solution was concentratedin vacuo to give the crude product which was used in the next stepwithout further purification (190 mg crude). ESI-MS [M+H]⁺: 459.1.

Synthesis ofN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-((N-(2,2,2-trifluoroethyl)sulfamoyl)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide

To a solution of1-((6-cyclopropyl-8-((N-(2,2,2-trifluoroethyl)sulfamoyl)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (190 mg crude from previous step) and(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride(109 mg, 0.46 mmol) in DMF (10 mL) was added HOBT (66 mg, 0.49 mmol),EDCI (94 mg, 0.49 mmol), and DIPEA (147 mg, 1.14 mmol). The resultingmixture was stirred at RT for 14 h. Water (30 mL) was added and themixture was extracted with EtOAc (40 mL×3). The combined organic layerswere washed with brine, dried over Na₂SO₄, and concentrated in vacuo togive the crude product which was purified with prep-TLC (DCM/MeOH=10/1)to giveN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-((N-(2,2,2-trifluoroethyl)sulfamoyl)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(18 mg, 7.4% over 3 steps). ESI-MS [M+H]⁺: 640.1. Purity: 91.16% (214nm), 93.03% (254 nm). ¹H NMR (400 MHz, DMSO): δ 8.62 (t, J=5.5 Hz, 1H),8.51 (s, 1H), 8.44 (s, 1H), 8.36 (s, 1H), 8.20 (d, J=7.2 Hz, 1H), 8.13(s, 1H), 7.87 (s, 1H), 7.09 (s, 1H), 6.76 (t, J=6.5 Hz, 1H), 5.74 (s,2H), 4.74-4.63 (m, 4H), 3.71-3.63 (m, 2H), 1.99-1.90 (m, 1H), 1.06-0.85(m, 2H), 0.71-0.66 (m, 2H).

Example 282

Synthesis of 2-iminopyridin-1(2H)-amine 2,4,6-trimethylbenzenesulfonate

To a stirred solution of O-(mesitylsulfonyl)hydroxylamine (12.57 g, 58.4mmol) in DCM (200 mL) was added pyridin-2-amine (5.5 g, 58.4 mmol) infour portions at 0° C. The mixture was stirred at 0° C. for 10 min andthen warmed to RT and stirred for 1 h. The reaction mixture wasconcentrated in vacuo to give 2-iminopyridin-1(2H)-amine2,4,6-trimethylbenzenesulfonate (18.07 g, yield: 100%) as a light brownsolid. ESI-MS [M+H]⁺: 110.2.

Synthesis of Ethyl [1,2,4]triazolo[1,5-a]pyridine-2-carboxylate

To a stirred solution of 2-iminopyridin-1(2H)-amine2,4,6-trimethylbenzenesulfonate (18.07 g, 58.4 mmol) in pyridine (70 mL)at RT was added ethyl 2-chloro-2-oxoacetate (15.9 g, 116.8 mmol)dropwise. The mixture was warmed to 100° C. and stirred for 16 h. Thereaction mixture was concentrated and diluted with water (200 mL),adjusted to pH 9-10 with saturated aqueous NaHCO₃, and extracted withEtOAc (150 mL×5). The combined organics were washed with brine (200mL×1), dried over Na₂SO₄, and concentrated to give the crude residue,which was triturated with EtOAc to give ethyl[1,2,4]triazolo[1,5-a]pyridine-2-carboxylate (7.0 g, yield: 63%) as ayellow solid. ESI-MS [M+H]⁺: 192.1.

Synthesis of [1,2,4]triazolo[1,5-a]pyridin-2-ylmethanol

To a stirred solution of ethyl[1,2,4]triazolo[1,5-a]pyridine-2-carboxylate (2.4 g, 12.55 mmol) in MeOH(20 mL) and THF (10 mL) was added NaBH₄ (950 mg, 25.1 mmol) portionwiseat 0° C. The mixture was stirred at RT for 2 h. The reaction mixture wasquenched with saturated aqueous NH₄Cl and concentrated in vacuo. Theresidue was dissolved in DCM/MeOH (100 mL), filtered, and the filtercake was rinsed with DCM/MeOH (50 mL). The combined filtrate wasconcentrated and purified by silica gel chromatography (EA/PE=1/1) togive [1,2,4]triazolo[1,5-a]pyridin-2-ylmethanol (1.6 g, yield: 85%) as ayellow solid. ESI-MS [M+H]⁺: 150.1.

Synthesis of 2-(chloromethyl)-[1,2,4]triazolo[1,5-a]pyridine

To a stirred solution of [1,2,4]triazolo[1,5-a]pyridin-2-ylmethanol (1.6g, 10.73 mmol) in DCM (30 mL) was added dropwise SOCl₂ (12.8 g, 107.3mmol) at 0° C. The mixture was stirred at RT for 1 h. The reactionmixture was concentrated and dried in vacuo to give2-(chloromethyl)-[1,2,4]triazolo[1,5-a]pyridine (1.8 g, yield: 100%) asa yellow solid. ESI-MS [M+H]⁺: 168.0.

Synthesis of Ethyl1-([1,2,4]triazolo[1,5-a]pyridin-2-ylmethyl)-1H-pyrazole-4-carboxylate

A mixture of 2-(chloromethyl)-[1,2,4]triazolo[1,5-a]pyridine (0.78 g,4.67 mmol), ethyl 1H-pyrazole-4-carboxylate (782 mg, 5.58 mmol) andCs₂CO₃ (2.27 g, 6.98 mmol) in DMF (10 mL) was stirred at RT for 2 h. Thereaction mixture was poured into water (50 mL) and extracted with EtOAc(50 mL×4). The combined organics were washed with water (150 mL×3) andbrine (150 mL×1), dried over Na₂SO₄, and concentrated to give the crudeproduct which was purified by silica gel chromatography (EA/PE=1/2) togive ethyl1-([1,2,4]triazolo[1,5-a]pyridin-2-ylmethyl)-1H-pyrazole-4-carboxylate(1.26 g, yield: 100%) as a white solid. ESI-MS [M+H]⁺: 272.1.

Synthesis of1-([1,2,4]triazolo[1,5-a]pyridin-2-ylmethyl)-1H-pyrazole-4-carboxylicAcid

To a solution of ethyl1-([1,2,4]triazolo[1,5-a]pyridin-2-ylmethyl)-1H-pyrazole-4-carboxylate(1.26 g, 4.64 mmol) in methanol (10 mL)/THF (10 mL)/H₂O (5 mL) was addedlithium hydroxide monohydrate (761 mg, 18.58 mmol). The mixture wasstirred at 50° C. for 1 h. The reaction was concentrated in vacuo toremove MeOH and THF. Then the mixture was diluted with water (40 mL),the pH was acidified to 5-6 using hydrochloric acid (2 M) and theprecipitate was collected and dried in vacuo to give1-([1,2,4]triazolo[1,5-a]pyridin-2-ylmethyl)-1H-pyrazole-4-carboxylicacid (720 mg, yield: 64%) as a white solid. ESI-MS [M+H]⁺: 244.1.

Synthesis of1-([1,2,4]triazolo[1,5-a]pyridin-2-ylmethyl)-N-((7-chloro-s-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide

A mixture of1-([1,2,4]triazolo[1,5-a]pyridin-2-ylmethyl)-1H-pyrazole-4-carboxylicacid (150 mg, 0.617 mmol),(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride(175 mg, 0.74 mmol), EDCI (235 mg, 1.23 mmol), HOBT (166 mg, 1.23 mmol)and DIPEA (477 mg, 3.70 mmol) in DMF (7 mL) was stirred at RT for 16 h.The reaction mixture was poured into water (70 mL) and the precipitatewas collected and purified by silica gel chromatography (DCM/MeOH=10/1)to give1-([1,2,4]triazolo[1,5-a]pyridin-2-ylmethyl)-N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-carboxamide(160 mg, yield: 61%) as a pale white solid. ESI-MS [M+H]⁺: 425.1.Purity: 99%. ¹H NMR (400 MHz, DMSO): δ 8.93 (d, J=6.8 Hz, 1H), 8.50-8.45(m, 1H), 8.32 (s, 1H), 8.22 (d, J=7.4 Hz, 1H), 7.86 (s, 1H), 7.79 (d,J=8.9 Hz, 1H), 7.72-7.63 (m, 1H), 7.20 (t, J=6.8 Hz, 1H), 6.77 (t, J=6.9Hz, 1H), 5.61 (s, 2H), 4.65 (d, J=5.2 Hz, 2H).

Example 283

Synthesis of2-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-2H-tetrazole-5-carboxylicAcid

A solution of ethyl2-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-2H-tetrazole-5-carboxylate(25 mg, 0.08 mmol) and LiOH.H₂O (7 mg, 0.160 mmol) in THF (2 mL),ethanol (2 mL), and H₂O (0.5 mL) was stirred at 40° C. overnight. Themixture was adjust to pH 1 using HCl (3 M). The mixture was thenconcentrated and used in the next reaction without further purification.ESI-MS [M+H]⁺: 285.1.

Synthesis ofN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-2-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-2H-tetrazole-5-carboxamide

A solution of2-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-2H-tetrazole-5-carboxylicacid (23 mg, crude from previous step),(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride(23 mg, 0.096 mmol), HOBT (22 mg, 0.16 mmol), EDCI (31 mg, 0.16 mmol)and DIPEA (31 mg, 0.24 mmol) in DMF (2 mL) was stirred at 40° C.overnight. The mixture was diluted with water (30 mL) and extracted withEtOAc (20 mL×3). The combined organic layers were washed with brine,dried over Na₂SO₄ and concentrated. The residue was purified byprep-HPLC to affordN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-2-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-2H-tetrazole-5-carboxamideas a white solid (21.8 mg, 47%, 2 steps). ESI-MS [M+H]⁺: 466.1. Purity:96.09% (214 nm), 97.06% (254 nm). ¹H NMR (400 MHz, DMSO): δ 9.29 (t,J=5.1 Hz, 1H), 8.44 (s, 1H), 8.36 (s, 1H), 8.21 (d, J=7.4 Hz, 1H), 7.94(s, 1H), 7.39 (d, J=9.3 Hz, 1H), 7.02 (d, J=9.3 Hz, 1H), 6.76 (t, J=6.8Hz, 1H), 6.07 (s, 2H), 4.72 (d, J=5.3 Hz, 2H), 1.96-1.90 (m, 1H),0.93-0.91 (m, 2H), 0.68-0.67 (m, 2H).

Example 284

Synthesis of 2-(chloromethyl)imidazo[1,2-a]pyridine

To a solution of pyridin-2-amine (5 g, 53.19 mmol) in DME (200 mL) wasadded 1,3-dichloropropan-2-one (20.2 g, 159.42 mmol) at RT. Theresulting reaction was stirred at 85° C. for 6 h. The solution wasquenched with saturated aqueous NaHCO₃ (200 mL) and extracted with EtOAc(150 mL×3). The combined organic layers were washed with brine, driedover Na₂SO₄, and concentrated in vacuo to give the crude, which waspurified by flash column chromatography to afford2-(chloromethyl)imidazo[1,2-a]pyridine (6 g, yield: 68%) as a lightyellow oil. ESI-MS [M+H]⁺: 167.2.

Synthesis of Ethyl1-(imidazo[1,2-a]pyridin-2-ylmethyl)-1H-pyrazole-4-carboxylate

To a solution of 2-(chloromethyl)imidazo[1,2-a]pyridine (3 g, 18.07mmol) in DMF (30 mL) was added ethyl 1H-pyrazole-4-carboxylate (3.04 g,21.68 mmol) and Cs₂CO₃ (17.67 g, 54.21 mmol) at RT. The resultingreaction was stirred at RT for 12 h. Water (300 mL) was added to thereaction, and the mixture was extracted with EtOAc (50 mL×3). Thecombined organic layers were washed with brine, dried over Na₂SO₄, andconcentrated in vacuo to give the crude, which was purified was purifiedby flash column chromatography to give ethyl1-(imidazo[1,2-a]pyridin-2-ylmethyl)-1H-pyrazole-4-carboxylate (3 g,yield: 61%) as a white solid. ESI-MS [M+H]⁺: 271.2.

Synthesis of1-(imidazo[1,2-a]pyridin-2-ylmethyl)-1H-pyrazole-4-carboxylic Acid

To a solution of ethyl1-(imidazo[1,2-a]pyridin-2-ylmethyl)-1H-pyrazole-4-carboxylate (3 g,11.11 mmol) in THF (20 mL) and water (20 mL) was added LiOH.H₂O (1.3 g,55.5 mmol). The mixture was stirred at RT for 6 h. The organic layer wasevaporated, and the water phase was acidified with 1N hydrochloric acidto pH, 3 and then extracted with DCM/MeOH (10/1, 10 mL×3). The combinedorganic layers were washed with brine, dried over Na₂SO₄, andconcentrated to give1-(imidazo[1,2-a]pyridin-2-ylmethyl)-1H-pyrazole-4-carboxylic acid (2 g,75% yield). ESI-MS [M+H]⁺: 243.2.

Synthesis ofN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-(imidazo[1,2-a]pyridin-2-ylmethyl)-1H-pyrazole-4-carboxamide

To a solution of1-(imidazo[1,2-a]pyridin-2-ylmethyl)-1H-pyrazole-4-carboxylic acid (150mg, 0.62 mmol), (7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanaminehydrochloride (190 mg, 0.81 mmol),

EDCI (178 mg, 0.93 mmol) and HOBT (126 mg, 0.93 mmol) in DMF (5 mL) wasadded DIPEA (240 mg, 1.86 mmol). The resulting reaction was stirred atRT for 12 h. H₂O (20 mL) was added to the reaction, and the mixture wasextracted with EtOAc (10 mL×3). The combined organic layers were washedwith brine, dried over Na₂SO₄, and concentrated in vacuo to give thecrude product which was purified by Prep-TLC (DMC/MeOH=10/1) to giveN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-(imidazo[1,2-a]pyridin-2-ylmethyl)-1H-pyrazole-4-carboxamide(60 mg, yield: 23%) as a white solid. ESI-MS [M+H]⁺: 424.2. Purity:97.15% (214 nm), 97.42% (254 nm). ¹H NMR (400 MHz, DMSO): δ 8.51 (d,J=6.7 Hz, 1H), 8.48-8.39 (m, 2H), 8.28-8.13 (m, 2H), 7.85 (d, J=5.3 Hz,2H), 7.50 (d, J=9.1 Hz, 1H), 7.28-7.17 (m, 1H), 6.87 (t, J=6.7 Hz, 1H),6.76 (t, J=6.9 Hz, 1H), 5.42 (s, 2H), 4.63 (d, J=5.1 Hz, 2H).

Example 285

Synthesis of 2-(chloromethyl)imidazo[1,2-b]pyridazine

A solution of pyridazin-3-amine (5 g, 52.6 mmol) and1,3-dichloropropan-2-one (8 g, 63.1 mmol) in DME (50 ml) was stirred at90° C. for 18 h. The reaction was quenched with saturated aqueous NaHCO₃and extracted by DCM/MeOH (5/1.4 L×3). The combined organic layer waswashed with brine, dried over Na₂SO₄, and concentrated to give the crudeproduct, which was purified by flash chromatography (DCM/MeOH=20/1) toafford 2-(chloromethyl)imidazo[1,2-b]pyridazine (1 g, yield: 11.5%) as ayellow solid. ESI-MS: [M+H]*, 168.1.

Synthesis of Ethyl1-(imidazo[1,2-b]pyridazin-2-ylmethyl)-1H-pyrazole-4-carboxylate

A mixture of 2-(chloromethyl)imidazo[1,2-b]pyridazine (300 mg, 1.8mmol), ethyl 1H-pyrazole-4-carboxylate (302 mg, 2.16 mmol) and Cs₂CO₃(1.76 g, 5.4 mmol) in DMF (5 mL) was stirred at RT for 18 h. Water (50mL) was added to the reaction, and the mixture was extracted by EtOAc(100 mL×3). The combined organic layers were washed by brine, dried overNa₂SO₄, and concentrated to give the crude product, which was purifiedby flash chromatography (DCM/MeOH=100/1) to afford ethyl1-(imidazo[1,2-b]pyridazin-2-ylmethyl)-1H-pyrazole-4-carboxylate (210mg, yield: 43%) as a white solid. ESI-MS: [M+H]*, 272.2.

Synthesis of1-(imidazo[1,2-b]pyridazin-2-ylmethyl)-1H-pyrazole-4-carboxylic Acid

A mixture of ethyl1-(imidazo[1,2-b]pyridazin-2-ylmethyl)-1H-pyrazole-4-carboxylate (180mg, 0.664 mmol) and LiOH.H₂O (82 mg, 2.0 mmol) in THF (6 mL) and H₂O (6mL) was stirred at RT for 3 h. The reaction mixture was concentrated togive the crude and the residue was adjusted to pH 3 with hydrochloricacid (3 M). The white solid precipitate was collected by filtration toafford 1-(imidazo[1,2-b]pyridazin-2-ylmethyl)-1H-pyrazole-4-carboxylicacid (130 mg, yield: 81%) as a white solid. ESI-MS: [M+H]*, 244.2.

Synthesis ofN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-(imidazo[1,2-b]pyridazin-2-ylmethyl)-1H-pyrazole-4-carboxamide

A mixture of1-(imidazo[1,2-b]pyridazin-2-ylmethyl)-1H-pyrazole-4-carboxylic acid (50mg, 0.2 mmol), (7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanaminehydrochloride (48 mg, 0.2 mmol), DIEA (103 mg, 0.8 mmol), and HATU (114mg, 0.3 mmol) in DMF (1.5 mL) was stirred at RT for 18 h. Water (30 mL)was added to the reaction, and the mixture was extracted with EtOAc (30ml×3). The combined organic layers were washed by brine, dried overNa₂SO₄, and concentrated to give the crude product which was purified byPrep-TLC (DCM/MeOH=10/1) to giveN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-(imidazo[1,2-b]pyridazin-2-ylmethyl)-1H-pyrazole-4-carboxamide(46 mg, 54%) as a white solid. ESI-MS: [M+H]*, 425.1. Purity: 92.66%(214 nm), 93.26% (254 nm). ¹H NMR (400 MHz, DMSO): δ 8.50 (d, J=3.6 Hz,1H), 8.45-8.39 (m, 2H), 8.25 (d, J=4.5 Hz, 2H), 8.21 (d, J=7.4 Hz, 1H),8.07 (d, J=9.2 Hz, 1H), 7.84 (s, 1H), 7.26-7.20 (m, 1H), 6.79-6.74 (m,1H), 5.47 (s, 2H), 4.63 (d, J=5.2 Hz, 2H).

Example 286

Synthesis of 2-(azidomethyl)imidazo[1,2-a]pyridine

A mixture of 2-(chloromethyl)imidazo[1,2-a]pyridine (4 g, 24.1 mmol) andNaN₃ (2.34 g, 36.15 mmol) in DMF (30 mL) was stirred at RT for 3 h.Water (300 mL) was added to the reaction, and the mixture was extractedwith EtOAc (50 mL×3). The combined organic layers were washed withbrine, dried over Na₂SO₄, and concentrated in vacuo to give the crudeproduct which was purified with silica gel chromatography (EA/PE=1/1) togive 2-(azidomethyl)imidazo[1,2-a]pyridine (3.6 g, yield: 86%) as ayellow solid. ESI-MS [M+H]⁺: 174.1.

Synthesis of Ethyl1-(imidazo[1,2-a]pyridin-2-ylmethyl)-1H-1,2,3-triazole-4-carboxylate

To a solution of 2-(azidomethyl)imidazo[1,2-a]pyridine (3.6 g, 20.8mmol) in t-BuOH/H₂O (10 mL/1 mL) was added ethyl propiolate (2.71 g,27.7 mmol), CuSO₄ (660 mg, 4.16 mmol) and sodium ascorbate (823 mg, 4.16mmol). The resulting reaction was stirred at RT for 3 h. The reactionmixture was then concentrated in vacuo. The residue was triturated withH₂O (30 mL) and filtered to give ethyl1-(imidazo[1,2-a]pyridin-2-ylmethyl)-1H-1,2,3-triazole-4-carboxylate(2.4 g, yield: 43%) as a yellow solid. ESI-MS [M+H]⁺: 272.2.

Synthesis of1-(imidazo[1,2-a]pyridin-2-ylmethyl)-1H-1,2,3-triazole-4-carboxylic Acid

A mixture of ethyl1-(imidazo[1,2-a]pyridin-2-ylmethyl)-1H-1,2,3-triazole-4-carboxylate(2.0 g, 7.38 mmol) and LiOH.H₂O (1.5 g, 36.9 mmol) in THF/H₂O (20 mL/20mL) was stirred at RT for 3 h. The reaction was evaporated, and theaqueous phase was acidified with 1N hydrochloric acid to pH 3 andextracted with EtOAc/MeOH (10/1, 50 mL×3). The combined organic layerswere washed with brine, dried over Na₂SO₄, and concentrated to give1-(imidazo[1,2-a]pyridin-2-ylmethyl)-1H-1,2,3-triazole-4-carboxylic acid(1.5 g, yield: 84%) as a yellow solid. ESI-MS [M+H]⁺: 244.2.

Synthesis ofN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-(imidazo[1,2-a]pyridin-2-ylmethyl)-1H-1,2,3-triazole-4-carboxamide

To a solution of1-(imidazo[1,2-a]pyridin-2-ylmethyl)-1H-1,2,3-triazole-4-carboxylic acid(150 mg, 0.62 mmol),(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride(190 mg, 0.81 mmol), EDCI (178 mg, 0.93 mmol) and HOBT (126 mg, 0.93mmol) in DMF (3 mL) was added DIPEA (240 mg, 1.86 mmol). The resultingreaction was stirred at RT for 12 h. Water (30 mL) was added to thereaction, and the mixture was extracted with EtOAc (30 mL×3). Thecombined organic layers were washed with brine, dried over Na₂SO₄, andconcentrated in vacuo. The crude product was purified by Prep-TLC(DCM/MeOH=10/1) to giveN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-(imidazo[1,2-a]pyridin-2-ylmethyl)-1H-1,2,3-triazole-4-carboxamideas a white solid. (50 mg, yield: 19%). ESI-MS [M+H]⁺: 425.1. Purity:94.17% (214 nm), 95.28% (254 nm). ¹H NMR (400 MHz, DMSO): δ 8.71 (t,J=5.4 Hz, 1H), 8.57 (s, 1H), 8.53 (d, J=6.8 Hz, 1H), 8.44 (d, J=2.4 Hz,1H), 8.21 (d, J=7.4 Hz, 1H), 7.94 (s, 1H), 7.51 (d, J=9.1 Hz, 1H),7.29-7.20 (m, 1H), 6.89 (t, J=6.4 Hz, 1H), 6.80-6.72 (m, 1H), 5.76 (s,2H), 4.70 (d, J=5.5 Hz, 2H).

Example 287

Synthesis of 2-(azidomethyl)-[1,2,4]triazolo[1,5-a]pyridine

A mixture of 2-(chloromethyl)-[1,2,4]triazolo[1,5-a]pyridine (1.0 g,5.98 mmol) and NaN₃ (427 mg, 6.57 mmol) in DMF (10 mL) was stirred at RTfor 5 h. The reaction mixture was poured into water (100 mL) andextracted with EtOAc (70 mL×3). The combined organics were washed withwater (30 mL×3) and brine (150 mL×1), dried over Na₂SO₄, concentratedand dried in vacuo to give2-(azidomethyl)-[1,2,4]triazolo[1,5-a]pyridine (1.04 g, yield: 100%) asa yellow solid which was used in next step directly. ESI-MS [M+H]⁺:175.2.

Synthesis of Ethyl1-([1,2,4]triazolo[1,5-a]pyridin-2-ylmethyl)-1H-1,2,3-triazole-4-carboxylate

To a stirred solution of 2-(azidomethyl)-[1,2,4] triazolo[1,5-a]pyridine(1.0 g, 5.74 mmol) in t-BuOH/H₂O (20 mL/2 mL) was added sodium ascorbate(594 mg, 3.0 mmol), CuSO₄ (479 mg, 3.0 mmol) and ethyl propiolate (646mg, 6.6 mmol) at 0° C. The reaction was stirred at RT for 2 h and thenconcentrated in vacuo. Water (40 mL) was added, and the mixture wasextracted with EtOAc (30 mL×3). The combined organics were washed withbrine (40 mL), dried over Na₂SO₄, concentrated, and purified by silicagel chromatography (EtOAc) to give ethyl 1-([1,2,4] triazolo[1,5-a]pyridin-2-ylmethyl)-1H-1,2,3-triazole-4-carboxylate (1.16 g, yield:74%). ESI-MS [M+H]⁺: 273.1.

Synthesis of1-([1,2,4]triazolo[1,5-a]pyridin-2-ylmethyl)-1H-1,2,3-triazole-4-carboxylicAcid

To a solution of ethyl 1-([1,2,4] triazolo[1,5-a]pyridin-2-ylmethyl)-1H-1,2,3-triazole-4-carboxylate (1.16 g, 4.26 mmol)in THF/MeOH/H₂O (8 mL/8 mL/4 mL) was added LiOH.H₂O (700 mg, 17.06mmol). The reaction mixture was stirred at 40° C. for 1 h. The reactionmixture was then concentrated and the water layer was adjusted to pH 4-5with hydrochloric acid (2 M). The white solid precipitate was collectedby filtration to get1-([1,2,4]triazolo[1,5-a]pyridin-2-ylmethyl)-1H-1,2,3-triazole-4-carboxylicacid (929 mg, yield: 89%) as a white solid. ESI-MS [M+H]⁺: 245.1.

Synthesis of1-([1,2,4]triazolo[1,5-a]pyridin-2-ylmethyl)-N-((7-chloro-s-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-1,2,3-triazole-4-carboxamide

To a solution of1-([1,2,4]triazolo[1,5-a]pyridin-2-ylmethyl)-1H-1,2,3-triazole-4-carboxylicacid (100 mg, 0.41 mmol) in DMF (5 mL) was added EDCI (157 mg, 0.820mmol), HOBT (111 mg, 0.820 mmol), DIPEA (265 mg, 2.05 mmol) and(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride(116 mg, 0.492 mmol). The reaction was stirred at RT for 16 h. Thereaction mixture was then poured into water (50 mL) and extracted withEtOAc (25 mL×3). The combined organics were washed with water (60 mL×3)and brine (60 mL×1), dried over Na₂SO₄, concentrated, and purified bysilica gel chromatography (DCM/MeOH=10/1) to give1-([1,2,4]triazolo[1,5-a]pyridin-2-ylmethyl)-N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(117 mg, yield: 67%) as a white solid. ESI-MS [M+H]⁺: 426.0. Purity:97.32% (214 nm), 96.53% (254 nm). ¹H NMR (400 MHz, DMSO): δ 8.95 (d,J=6.8 Hz, 1H), 8.77 (t, J=5.4 Hz, 1H), 8.67 (s, 1H), 8.45 (d, J=2.4 Hz,1H), 8.21 (d, J=7.4 Hz, 1H), 7.81 (d, J=8.9 Hz, 1H), 7.73-7.65 (m, 1H),7.21 (t, J=6.9, 1.2 Hz, 1H), 6.80-6.73 (m, 1H), 5.98 (s, 2H), 4.72 (d,J=5.5 Hz, 2H).

Example 288

Synthesis of Ethyl1-((6-chloroimidazo[1,2-b]pyridazin-2-yl)methyl)-1H-imidazole-4-carboxylate

A solution of 6-chloro-2-(chloromethyl)imidazo[1,2-b]pyridazine (500 mg,2.49 mmol), ethyl 1H-imidazole-4-carboxylate (522 mg, 3.73 mmol), andCs₂CO₃ (1.6 g, 4.97 mmol) in DMF (10 mL) was stirred at RT overnight.The mixture was diluted with water (100 mL) and extracted with EtOAc (50mL×3). The combined organic layers were washed with brine, dried overNa₂SO₄, and concentrated. The crude product was purified by Prep-TLC(DCM/MeOH=12/1) to afford ethyl1-((6-chloroimidazo[1,2-b]pyridazin-2-yl)methyl)-1H-imidazole-4-carboxylateas a white solid (130 mg, 17%). ESI-MS [M+H]⁺: 306.1.

Synthesis of Ethyl1-((6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methyl)-1H-imidazole-4-carboxylate

A solution of ethyl1-((6-chloroimidazo[1,2-b]pyridazin-2-yl)methyl)-1H-imidazole-4-carboxylate(130 mg, 0.426 mmol), cyclopropylboronic acid (73 mg, 0.852 mmol),Pd(OAc)₂ (29 mg, 0.128 mmol), K₃PO₄ (181 mg, 0.852 mmol) and SPhos (52mg, 0.128 mmol) in toluene (5 mL) and H₂O (0.5 mL) was stirred at 90° C.under N₂ for 3 h. The mixture was cooled to RT, filtered, and the filtercake was washed with DCM/MeOH (3/1, 50 mL). The filtrate wasconcentrated and purified by Prep-TLC (DCM/MeOH=10/1) to afford ethyl1-((6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methyl)-1H-imidazole-4-carboxylateas a yellow solid (80 mg, 61%). ESI-MS [M+H]⁺: 312.2.

Synthesis of1-((6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methyl)-1H-imidazole-4-carboxylicAcid

A solution of ethyl1-((6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methyl)-1H-imidazole-4-carboxylate(40 mg, 0.128 mmol) and LiOH.H₂O (11 mg, 0.256 mmol) in THF (2 mL) andH₂O (2 mL) was stirred at 60° C. for 2 h. The reaction mixture wasadjusted to pH 5 with aqueous hydrochloric acid (3 M). The mixture wasconcentrated in vacuo to give the crude product which was used into thenext reaction without further purification (55 mg crude). ESI-MS [M+H]⁺:284.1.

Synthesis ofN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methyl)-1H-imidazole-4-carboxamide

A solution of1-((6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methyl)-1H-imidazole-4-carboxylicacid (55 mg crude from previous step),(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride(36 mg, 0.154 mmol), HOBT (70 mg, 0.518 mmol), EDCI (99 mg, 0.516 mmol)and DIPEA (100 mg, 0.771 mmol) in DMF (3 mL) was stirred at 60° C. for 5h. The reaction was poured into H₂O (25 mL) and a white solidprecipitated out. The mixture was filtered, and the filter cake waswashed by MeOH (5 mL) to affordN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methyl)-1H-imidazole-4-carboxamideas a white solid (18.6 mg, 31%, 2 steps). ESI-MS [M+H]⁺: 465.1. Purity:97.37% (214 nm), 97.90% (254 nm). ¹H NMR (400 MHz, DMSO): δ 8.44 (d,J=2.2 Hz, 1H), 8.20 (d, J=7.4 Hz, 1H), 8.12 (s, 1H), 8.00 (t, J=5.4 Hz,1H), 7.93 (d, J=9.4 Hz, 1H), 7.79 (s, 1H), 7.70 (s, 1H), 7.09 (d, J=9.5Hz, 1H), 6.75 (t, J=6.9 Hz, 1H), 5.33 (s, 2H), 4.66 (d, J=5.5 Hz, 2H),2.22-2.13 (m, 1H), 1.08-1.03 (m, 2H), 0.98-0.94 (m, 2H).

Example 289

Synthesis of 6-chloro-2-(chloromethyl)imidazo[1,2-b]pyridazine

A solution of 6-chloropyridazin-3-amine (2.58 g, 20 mmol) and1,3-dichloropropan-2-one (3.04 g, 24 mmol) in DME (30 mL) was stirred at90° C. overnight. The mixture was concentrated and purified by flashcolumn chromatography (PE/EtOAc=1/4) to afford6-chloro-2-(chloromethyl)imidazo[1,2-b]pyridazine as a yellow solid(1.37 g, 34%). ESI-MS [M+H]⁺: 202.0.

Synthesis of Ethyl2-((6-chloroimidazo[1,2-b]pyridazin-2-yl)methyl)-2H-tetrazole-5-carboxylate

A solution of 6-chloro-2-(chloromethyl)imidazo[1,2-b]pyridazine (201 mg,1.0 mmol), ethyl 2H-tetrazole-5-carboxylate (213 mg, 1.5 mmol) andCs₂CO₃ (489 mg, 1.5 mmol) in DMF (5 mL) was stirred at 60° C. overnight.The mixture was diluted with water (50 mL) and extracted with EtOAc (30mL×5). The combined organic layers were washed with brine, dried overNa₂SO₄ and concentrated. The residue was purified by flash columnchromatography (DCM/MeOH=30/1) to afford ethyl2-((6-chloroimidazo[1,2-b]pyridazin-2-yl)methyl)-2H-tetrazole-5-carboxylateas a white solid (140 mg, 45%). ESI-MS [M+H]⁺: 308.0.

Synthesis of Ethyl2-((6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methyl)-2H-tetrazole-5-carboxylate

A solution of ethyl2-((6-chloroimidazo[1,2-b]pyridazin-2-yl)methyl)-2H-tetrazole-5-carboxylate(140 mg, 0.456 mmol), cyclopropylboronic acid (78 mg, 0.912 mmol),Pd(OAc)₂ (31 mg, 0.137 mmol), K₃PO₄ (193 mg, 0.912 mmol) and SPhos (56mg, 0.137 mmol) in toluene (5 mL) and H₂O (0.5 mL) was stirred at 90° C.under N₂ for 3 h. The mixture was cooled to RT, filtered, and the filtercake was washed with DCM/MeOH (3/1, 50 mL). The filtrate wasconcentrated and purified by Prep-TLC (DCM/MeOH=40/1) to afford ethyl2-((6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methyl)-2H-tetrazole-5-carboxylateas a white solid (44 mg, 31%). ESI-MS [M+H]⁺: 314.2.

Synthesis of2-((6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methyl)-2H-tetrazole-5-carboxylicAcid

A solution of ethyl2-((6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methyl)-2H-tetrazole-5-carboxylate(40 mg, 0.128 mmol) and LiOH*H₂O (11 mg, 0.256 mmol) in THF (2 mL)/H₂O(2 mL) was stirred at 50° C. for 2 h. The reaction mixture wasconcentrated to remove THF. The residue was adjusted to pH 5 using 3 Mhydrochloric acid. Then the mixture was concentrated to give2-((6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methyl)-2H-tetrazole-5-carboxylicacid, which was used into the next step without further purification (60mg crude). ESI-MS [M+H]⁺: 286.2.

Synthesis ofN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-2-((6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methyl)-2H-tetrazole-5-carboxamide

A solution of2-((6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methyl)-2H-tetrazole-5-carboxylicacid (60 mg crude from previous step),(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride(37 mg, 0.154 mmol), HOBT (70 mg, 0.518 mmol), EDCI (99 mg, 0.516 mmol)and DIPEA (100 mg, 0.771 mmol) in DMF (3 mL) was stirred at 40° C.overnight. The reaction mixture was poured into H₂O (30 mL) and whitesolid was precipitated out. The mixture was filtered, and the filtercake was washed with MeOH (5 mL) to affordN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-2-((6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methyl)-2H-tetrazole-5-carboxamideas a white solid (10.1 mg, 17%, over 2 steps). MS [M+H]⁺: 467.1. Purity:94.54% (214 nm), 95.52% (254 nm). ¹H NMR (400 MHz, DMSO): δ 9.30 (t,J=5.3 Hz, 1H), 8.44 (d, J=1.7 Hz, 1H), 8.30 (s, 1H), 8.21 (d, J=7.4 Hz,1H), 7.92 (d, J=9.4 Hz, 1H), 7.12 (d, J=9.5 Hz, 1H), 6.77 (t, J=6.9 Hz,1H), 6.10 (s, 2H), 4.72 (d, J=5.4 Hz, 2H), 2.21-2.15 (m, 1H), 1.09-1.05(m, 2H), 1.00-0.96 (m, 2H)

Example 290

Synthesis of 2-(chloromethyl)imidazo[1,2-b]pyridazine

To a solution of pyridazin-3-amine (5 g, 52.6 mmol) in DME (50 mL) wasadded 1,3-dichloropropan-2-one (8 g, 63.2 mmol). After stirring at 90°C. for 12 h, the mixture was cooled to RT and concentrated to give thecrude product, which was purified by silica gel chromatography(PE/EtOAc=10/3) to give the product as white solid (6 g, yield: 68%).ESI-MS [M+H]⁺: 168.6.

Synthesis of 2-(azidomethyl)imidazo[1,2-b]pyridazine

To a mixture of 2-(chloromethyl)imidazo[1,2-b]pyridazine (300 mg, 1.8mmol) in DMF (5 mL) at 0° C. was added NaN₃ (175 mg, 2.7 mmol). Themixture was stirred at RT for 18 h. Water (50 mL) was added and themixture was extracted with EtOAc (30 mL×3). The combined organic layerswere washed with water (50 mL) and brine (50 mL), dried over Na₂SO₄, andconcentrated to give the crude product which was purified by silica gelchromatography (PE/EtOAc=10/3) to give the product as yellow oil (240mg, yield: 77%). ESI-MS [M+H]⁺: 175.2.

Synthesis of Ethyl1-(imidazo[1,2-b]pyridazin-2-ylmethyl)-1H-1,2,3-triazole-4-carboxylate

To a solution 2-(azidomethyl)imidazo[1,2-b]pyridazine (240 mg, 1.38mmol) in t-BuOH/H₂O (10 mL/1 mL) was added sodium ascorbate (55 mg, 0.28mmol), CuSO₄ (45 mg, 0.28 mmol) and ethyl propiolate (162 mg, 1.66mmol). After stirring at RT for 3 h, H₂O (10 mL) was added and themixture was extracted with EtOAc (10 mL×3). The combined organic layerswere washed with brine (10 mL), dried over Na₂SO₄, and concentrated togive the crude product which was purified by silica gel chromatography(MeOH/DCM=1/10) to give the product as white solid (353 mg, yield: 94%).ESI-MS [M+H]⁺: 273.1.

Synthesis of1-(imidazo[1,2-b]pyridazin-2-ylmethyl)-1H-1,2,3-triazole-4-carboxylicAcid

To a solution of ethyl1-(imidazo[1,2-b]pyridazin-2-ylmethyl)-1H-1,2,3-triazole-4-carboxylate(353 mg, 1.3 mmol) in THF/EtOH/H2O (6 mL/6 mL/2 mL) was added LiOH H₂O(266 mg, 6.5 mmol). The mixture was stirred at RT for 1 h. Water (5 mL)was added and the mixture was extracted with CHCl₃/i-PrOH (3/1, 10mL×5). The combined organic layers were washed with brine (10 mL), driedwith Na₂SO₄, and concentrated to give the crude product as a white solid(190 mg, yield: 60%). This material was used in next step directly.ESI-MS [M+H]⁺: 245.1.

Synthesis ofN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-(imidazo[1,2-b]pyridazin-2-ylmethyl)-1H-1,2,3-triazole-4-carboxamide

A mixture of1-(imidazo[1,2-b]pyridazin-2-ylmethyl)-1H-1,2,3-triazole-4-carboxylicacid (70 mg 0.29 mmol), HATU (163 mg, 0.43 mmol), DIPEA (111 mg, 0.86mmol), and (7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanaminehydrochloride (80 mg, 0.34 mmol) in DMF (3 mL) was stirred at RT for 12h. Water (30 mL) was added and the mixture was extracted with EtOAc (30mL×6). The combined organic layers were washed with water (20 mL×3) andbrine (20 mL), dried over Na₂SO₄, and concentrated to give the crudeproduct which was purified by prep-TLC (MeOH/DCM=1/10) to give theproduct as white solid (50 mg, yield: 41%). ESI-MS [M+H]⁺: 426.1.Purity: 100% (214 nm), 100% (254 nm). ¹H NMR (400 MHz, DMSO): δ 8.71 (t,J=5.4 Hz, 1H), 8.60 (s, 1H), 8.52 (d, J=4.4 Hz, 1H), 8.44 (d, J=2.2 Hz,1H), 8.36 (s, 1H), 8.21 (d, J=7.4 Hz, 1H), 8.09 (d, J=8.7 Hz, 1H),7.28-7.21 (m, 1H), 6.76 (t, J=6.9 Hz, 1H), 5.81 (s, 2H), 4.70 (d, J=5.5Hz, 2H).

Example 291

Synthesis of Methyl1-(imidazo[1,2-b]pyridazin-2-ylmethyl)-1H-imidazole-4-carboxylate

To a solution of 2-(chloromethyl)imidazo[1,2-b]pyridazine (1.0 g, 5.98mmol) in DMF (10 mL) was added Cs₂CO₃ (2.92 g, 8.98 mmol) and methyl1H-imidazole-4-carboxylate (904 mg, 7.18 mmol) under N₂ atmosphere.After stirring at RT for 18 h, H₂O (100 mL) was added. The mixture wasextracted with EtOAc (100 mL×3). The combined organic layers were washedwith brine, dried over Na₂SO₄, and concentrated to give the crude, whichwas purified by prep-TLC (MeOH/DCM=1/10) to give methyl1-(imidazo[1,2-b]pyridazin-2-ylmethyl)-1H-imidazole-4-carboxylate as awhite solid (600 mg, yield: 39%). ESI-MS [M+H]⁺: 258.3.

Synthesis of1-(imidazo[1,2-b]pyridazin-2-ylmethyl)-1H-imidazole-4-carboxylic Acid

To a solution of methyl1-(imidazo[1,2-b]pyridazin-2-ylmethyl)-1H-imidazole-4-carboxylate (257mg, 1.0 mmol) in THF/H₂O (10 mL/10 mL) was added LiOH H₂O (253 mg, 6.0mmol). The reaction mixture was stirred at RT for 1 h. The reaction wasconcentrated to remove THF, and the residue was adjusted to pH 3 usinghydrochloric acid (1 M). The resulting precipitate was collected byfiltration to give the product as a white solid (130 mg, yield: 53.4%).ESI-MS [M+H]⁺: 244.1.

Synthesis ofN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-(imidazo[1,2-b]pyridazin-2-ylmethyl)-1H-imidazole-4-carboxamide

A mixture of1-(imidazo[1,2-b]pyridazin-2-ylmethyl)-1H-imidazole-4-carboxylic acid(70 mg 0.29 mmol), HATU (164 mg, 0.43 mmol), and DIPEA (111 mg, 0.86mmol) in DMF (3 mL) was stirred at RT for 20 min, then a solution of(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride(82 mg, 0.35 mmol) in 2 mL was added. The resulting reaction was stirredat RT for 12 h. H₂O (50 mL) was added and the mixture was extracted withEtOAc (30 mL×3). The combined organic layers were washed with brine,dried over Na₂SO₄, and concentrated in vacuo. The crude product waspurified by Prep-TLC (MeOH/DCM=1/10) to giveN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-(imidazo[1,2-b]pyridazin-2-ylmethyl)-1H-imidazole-4-carboxamideas a white solid. (50 mg, yield: 41%). ESI-MS [M+H]⁺: 425.1. Purity:95.85% (214 nm), 96.36% (254 nm). ¹H NMR (400 MHz, DMSO): δ 8.53-8.48(m, 1H), 8.44 (d, J=2.4 Hz, 1H), 8.28 (s, 1H), 8.20 (d, J=7.4 Hz, 1H),8.08 (d, J=9.2 Hz, 1H), 8.01 (t, J=5.5 Hz, 1H), 7.82 (d, J=1.0 Hz, 1H),7.73 (d, J=1.0 Hz, 1H), 7.27-7.20 (m, 1H), 6.80-6.71 (m, 1H), 5.39 (s,2H), 4.67 (d, J=5.5 Hz, 2H).

Example 292

Synthesis of 6-(bromomethyl)quinoxaline

To a solution of 6-methylquinoxaline (5 g, 34.7 mmol) in DCE (100 mL)was added NBS (7.12 g, 40 mmol) and benzoyl peroxide (840 mg, 3.47mmol). The reaction mixture was stirred at 85° C. for 16 h undernitrogen. H₂O (100 mL) was added, and the mixture was extracted with DCM(150 mL×3). The combine organic layers were washed with brine, driedover Na₂SO₄, and concentrated in vacuo to give the crude product whichwas purified by silica gel chromatography (PE/EtOAc=1/1) to give6-(bromomethyl)quinoxaline as a yellow solid. (5.5 g, 71%). ESI-MS[M+H]⁺: 224.1.

Synthesis of 6-(bromomethyl)quinoxaline

A mixture of 6-(bromomethyl)quinoxaline (3 g, 13.5 mmol) and NaN3 (1.2g, 18.5 mmol) in DMF (50 mL) was stirred at RT for 12 h. The reactionwas diluted with H₂O (500 mL) and extracted with EtOAc (70 mL×3). Thecombined organic layers were washed with brine, dried over Na₂SO₄, andconcentrated in vacuo to give 6-(azidomethyl)quinoxaline as a yellowsolid which was used in the next step without further purification. (2.5g crude). ESI-MS [M+H]⁺: 186.2.

Synthesis of Ethyl1-(quinoxalin-6-ylmethyl)-1H-1,2,3-triazole-4-carboxylate

To a solution of 6-(azidomethyl)quinoxaline (2.5 g crude from previousstep) and ethyl propiolate (1.58 g, 16.2 mmol) in t-BuOH/H₂O (15 mL/15mL) was added CuSO₄ (427 mg, 2.7 mmol) and sodium ascorbate (537 mg, 2.7mmol) at RT. The resulting mixture was stirred at RT for 2 h. Thereaction was diluted with H₂O (70 mL) and extracted with DCM/MeOH (10/1,70 mL×3). The combined organic layers were washed with brine, dried overNa₂SO₄, and concentrated in vacuo to give the crude product which waspurified by silica gel chromatography (DCM/MeOH=15/1) to give ethyl1-(quinoxalin-6-ylmethyl)-1H-1,2,3-triazole-4-carboxylate as a yellowsolid (1.5 g, 39% over 2 steps). ESI-MS [M+H]⁺: 284.2.

Synthesis of 1-(quinoxalin-6-ylmethyl)-1H-1,2,3-triazole-4-carboxylicAcid

A mixture of ethyl1-(quinoxalin-6-ylmethyl)-1H-1,2,3-triazole-4-carboxylate (1 g, 3.53mmol) and LiOH.H₂O (444 mg, 10.56 mmol) in THF/H₂O (10 mL/5 mL) wasstirred at RT for 12 h. The reaction was concentrated to remove THF. ThepH of residue was adjusted to around 3 using hydrochloric acid, andwhite solid precipitated out. The suspension was filtered to give1-(quinoxalin-6-ylmethyl)-1H-1,2,3-triazole-4-carboxylic acid as a whitesolid which was used in next step directly (650 mg, 72%). ESI-MS [M+H]⁺:256.2.

Synthesis ofN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-(quinoxalin-6-ylmethyl)-1H-1,2,3-triazole-4-carboxamide

To a solution of1-(quinoxalin-6-ylmethyl)-1H-1,2,3-triazole-4-carboxylic acid (100 mg,0.39 mmol) and (7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanaminehydrochloride (110.5 mg, 0.47 mmol) in DMF (5 mL) was added HOBT (81 mg,0.6 mmol), EDCI (115 mg, 0.6 mmol) and DIPEA (151 mg, 1.17 mmol). Theresulting mixture was stirred at RT for 12 h. The reaction was dilutedwith H₂O (25 mL) and extracted with EtAOc (40 mL×5). The combinedorganic layers were washed with brine, dried over Na₂SO₄, andconcentrated in vacuo to give the crude product which was purified byPrep-TLC (DCM/MeOH=8/1) to giveN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-(quinoxalin-6-ylmethyl)-1H-1,2,3-triazole-4-carboxamideas a white solid (35 mg, 20.6%). ESI-MS [M+H]⁺: 436.8. Purity: 100% (214nm) 99.16% (254 nm). ¹H NMR (400 MHz, DMSO): δ 8.97 (s, 2H), 8.76 (s,2H), 8.47 (d, J=2.3, 1H), 8.21 (d, J=7.4, 1H), 8.12 (d, J=8.6, 1H), 8.03(s, 1H), 7.79 (dd, J=8.7, 1.8, 1H), 6.77 (t, J=6.9, 1H), 5.95 (s, 2H),4.71 (d, J=5.4, 2H).

Example 293

Synthesis of Ethyl 1-(quinoxalin-6-ylmethyl)-1H-pyrazole-4-carboxylate

To a solution of 6-(bromomethyl)quinoxaline (3 g, 13.5 mmol) in MeCN (50ml) was added ethyl 1H-pyrazole-4-carboxylate (2.84 g, 20.3 mmol) andK₂CO₃ (5.6 g, 40.5 mmol) at RT. The reaction was stirred at RT for 12 h.H₂O (100 mL) was added, and the mixture was extracted with EtOAc (50mL×3). The combined organic layers were washed with brine, dried overNa₂SO₄, and concentrated in vacuo to give the crude product which waspurified by silica gel chromatography (DMC/MeOH=20/1) to give ethyl1-(quinoxalin-6-ylmethyl)-1H-pyrazole-4-carboxylate (1 g, yield: 26%) asa yellow solid. ESI-MS [M+H]⁺: 283.2.

Synthesis of 1-(quinoxalin-6-ylmethyl)-1H-pyrazole-4-carboxylic Acid

To a solution of ethyl1-(quinoxalin-6-ylmethyl)-1H-pyrazole-4-carboxylate (1 g, 3.5 mmol) inTHF (30 mL) and water (30 mL) was added LiOH.H₂O (441 mg, 10.5 mmol).The mixture was stirred at RT for 13 h. The organic layer wasevaporated, and the aqueous phase was acidified with 1N HCl to around pH4. The resulting precipitate was collected by filtration to give1-(quinoxalin-6-ylmethyl)-1H-pyrazole-4-carboxylic acid as a white solidwhich was used in next step directly (400 mg, yield: 45%). ESI-MS[M+H]⁺: 255.2.

Synthesis ofN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-(quinoxalin-6-ylmethyl)-1H-pyrazole-4-carboxamide

To a solution of 1-(quinoxalin-6-ylmethyl)-1H-pyrazole-4-carboxylic acid(100 mg, 0.39 mmol),(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride(139 mg, 0.59 mmol), EDCI (114 mg, 0.59 mmol) and HOBT (80 mg, 0.59mmol) in DMF (5 mL) was added DIPEA (151 mg, 1.17 mmol). The resultingreaction was stirred at RT for 12 h. H₂O (50 mL) was added, and themixture was extracted with EtOAc (30 mL×3). The combined organic layerswere washed with brine, dried over Na₂SO₄, and concentrated in vacuo togive the crude product which was purified by Prep-TLC (DMC/MeOH=10/1) togiveN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-(quinoxalin-6-ylmethyl)-1H-pyrazole-4-carboxamide(50 mg, yield: 29%) as a white solid. ESI-MS [M+H]⁺: 435.8. Purity:97.58 (214 nm), 97.29 (254 nm). ¹H NMR (400 MHz, DMSO): δ 8.95 (s, 2H),8.51-8.44 (m, 2H), 8.36 (s, 1H), 8.22 (d, J=7.4 Hz, 1H), 8.09 (d, J=8.7Hz, 1H), 7.92 (d, J=13.1 Hz, 2H), 7.72 (dd, J=8.6, 1.9 Hz, 1H),6.80-6.74 (m, 1H), 5.64 (s, 2H), 4.64 (d, J=5.2 Hz, 2H).

Example 294

Synthesis of Ethyl8-bromo-6-chloroimidazo[1,2-b]pyridazine-2-carboxylate

A mixture of 4-bromo-6-chloropyridazin-3-amine (25 g, 121 mmol) andethyl 3-bromo-2-oxopropanoate (47 g, 242.0 mmol) in EtOH (300 mL) wasstirred at 80° C. for 16 h under N₂. The mixture was then concentratedin vacuo, diluted with saturated aqueous NaHCO₃ solution (500 mL), andextracted with EtOAc (200 mL×3). The combined organic layer was washedwith brine, dried over Na₂SO₄, and concentrated in vacuo. The residuewas purified by flash column chromatography (DCM/MeOH=20/1) to giveethyl 8-bromo-6-chloroimidazo[1,2-b]pyridazine-2-carboxylate as a yellowsolid (6.5 g, yield: 18%). ESI-MS [M+H]⁺: 304.1.

Synthesis of Ethyl8-((tert-butoxycarbonyl)amino)-6-chloroimidazo[1,2-b]pyridazine-2-carboxylate

A mixture of ethyl8-bromo-6-chloroimidazo[1,2-b]pyridazine-2-carboxylate (6.0 g, 19.8mmol), NH₂Boc (2.9 g, 24.8 mmol), Pd(OAc)₂ (224 mg, 1.0 mmol), XantPhos(579 mg, 1.0 mmol), and Cs₂CO₃ (19.4 g, 59.4 mmol) in dioxane (150 mL)was stirred at 95° C. for 16 h under N₂. The mixture was cooled, water(200 mL) was added, and the mixture was extracted with EtOAc (100 mL×3).The combined organic layer was washed with brine, dried over Na₂SO₄ andconcentrated in vacuo. The residue was purified by flash columnchromatography (DCM/MeOH=20/1) to give ethyl8-((tert-butoxycarbonyl)amino)-6-chloroimidazo[1,2-b]pyridazine-2-carboxylate(3.0 g, yield: 44%) as a light yellow solid. ESI-MS [M+H]⁺: 341.1.

Synthesis of Ethyl8-((tert-butoxycarbonyl)amino)imidazo[1,2-b]pyridazine-2-carboxylate

To a solution of ethyl8-((tert-butoxycarbonyl)amino)-6-chloroimidazo[1,2-b]pyridazine-2-carboxylate(2.8 g, 8.24 mmol) in EtOH/DCM (30 mL/30 mL) was added Pd/C (280 mg).The mixture was stirred under hydrogen atmosphere at RT for 16 h. Themixture was filtered and the solid was washed with DCM/MeOH (10/1, 60mL). Then the filtrate was concentrated and purified by flash columnchromatography (DCM/MeOH=0-10%) to give ethyl8-((tert-butoxycarbonyl)amino)imidazo[1,2-b]pyridazine-2-carboxylate(2.2 g, yield: 87%) as a yellow solid. ESI-MS [M+H]⁺: 307.1.

Synthesis of tert-butyl(2-(hydroxymethyl)imidazo[1,2-b]pyridazin-8-yl)carbamate

To a mixture of ethyl8-((tert-butoxycarbonyl)amino)imidazo[1,2-b]pyridazine-2-carboxylate(2.0 g, 6.54 mmol) in dry THF (30 mL) was added DIBAL-H (16.3 mL, 16.3mmol) at 0° C. The mixture was stirred at 0° C. for 2 h under N₂ andthen quenched with water (100 mL). The mixture was filtered andextracted with EtOAc (50 mL×3). The combined organic layer was washedwith brine, dried over Na₂SO₄, and concentrated in vacuo. The residuewas purified by flash column chromatography (DCM/MeOH=30:1) to givetert-butyl (2-(hydroxymethyl)imidazo[1,2-b]pyridazin-8-yl)carbamate(1.25 g, yield: 72%) as a yellow solid. ESI-MS [M+H]⁺: 265.2.

Synthesis of tert-butyl(2-(azidomethyl)imidazo[1,2-b]pyridazin-8-yl)carbamate

To a mixture of tert-butyl(2-(hydroxymethyl)imidazo[1,2-b]pyridazin-8-yl)carbamate (1.0 g, 3.78mmol) and DPPA (2.7 g, 9.85 mmol) in DCM (15 mL) was added DBU (1.50 g,9.85 mmol) at 0° C. under N₂. The mixture was stirred at RT for 16 h,then diluted with water (50 mL) and extracted with DCM (30 mL×5). Thecombined organic layer was washed with brine, dried over Na₂SO₄, andconcentrated in vacuo. The residue was purified by flash columnchromatography (DCM/MeOH=20:1) to give tert-butyl(2-(azidomethyl)imidazo[1,2-b]pyridazin-8-yl)carbamate (500 mg, yield:46%) as a colorless oil. ESI-MS [M+H]⁺: 290.2.

Synthesis of Ethyl1-((8-((tert-butoxycarbonyl)amino)imidazo[1,2-b]pyridazin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate

A mixture of tert-butyl(2-(azidomethyl)imidazo[1,2-b]pyridazin-8-yl)carbamate (500 mg, 1.73mmol), ethyl propiolate (254 mg, 2.60 mmol), CuSO₄ (138 mg, 0.87 mmol)and sodium ascorbate (172 mg, 0.87 mmol) in t-BuOH/H₂O (10 mL/5 mL) wasstirred at RT for 16 h. The reaction mixture was diluted with water (50mL) and extracted with DCM (30 mL×3). The combined organic layer waswashed with brine, dried over Na₂SO₄ and concentrated in vacuo. Theresidue was purified by flash column chromatography (DCM/MeOH=20/1) togive ethyl1-((8-((tert-butoxycarbonyl)amino)imidazo[1,2-b]pyridazin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(350 mg, yield: 52%) as a white solid. ESI-MS [M+H]⁺: 388.2.

Synthesis of1-((8-((tert-butoxycarbonyl)amino)imidazo[1,2-b]pyridazin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicAcid

A solution of ethyl1-((8-((tert-butoxycarbonyl)amino)imidazo[1,2-b]pyridazin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(251 mg, 0.65 mmol) and LiOH.H₂O (40 mg, 0.97 mmol) in THF/water (5 mL/5mL) was stirred at RT for 3 h. The reaction mixture was adjusted to pH 5using hydrochloric acid (1 M) and concentrated in vacuo at 20° C. togive lithium5-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1,3,4-oxadiazole-2-carboxylateas a yellow solid, which was used in next step without furtherpurification (290 mg, yield: 100%). ESI-MS [M+H]⁺: 360.1.

Synthesis of tert-butyl(2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-b]pyridazin-s-yl)carbamate

A mixture of1-((8-((tert-butoxycarbonyl)amino)imidazo[1,2-b]pyridazin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (80 mg crude from previous step),(7-chloroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride (63 mg,0.27 mmol), EDCI (63 mg, 0.33 mmol), HOBt (44 mg, 0.33 mmol) and DIPEA(85 mg, 0.66 mmol) in DMF (10 mL) was stirred at 50° C. for 16 h. Themixture was concentrated to remove DMF, diluted with DCM/MeOH (300 mL,10/1), and washed with water (100 mL×2). The organic layer wasseparated, dried over Na₂SO₄, and concentrated in vacuo to give thecrude product which was purified by silica gel chromatography(DCM/MeOH=10/1) to give tert-butyl(2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-b]pyridazin-8-yl)carbamate(80 mg, yield: 67%) as a light yellow solid. ESI-MS [M+H]⁺: 541.2.

Synthesis of1-((8-aminoimidazo[1,2-b]pyridazin-2-yl)methyl)-N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-1,2,3-triazole-4-carboxamide

A mixture of tert-butyl(2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-b]pyridazin-8-yl)carbamate(80 mg, 0.15 mmol) in HCl/dioxane (4.0 M, 5 mL) was stirred at RT for 16h. The mixture was concentrated to give1-((8-aminoimidazo[1,2-b]pyridazin-2-yl)methyl)-N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(100 mg, crude) as a light yellow solid. ESI-MS [M+H]⁺: 441.2.

Synthesis of1-((8-(4H-1,2,4-triazol-4-yl)imidazo[1,2-b]pyridazin-2-yl)methyl)-N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-1,2,3-triazole-4-carboxamide

A mixture of1-((8-aminoimidazo[1,2-b]pyridazin-2-yl)methyl)-N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-1,2,3-triazole-4-carboxamide (88 mg, 0.20 mmol,crude from previous step) and trimethoxymethane (2.0 mL) in CH₃CN (8.0mL) was stirred at reflux under N₂ for 6 h. The reaction was cooled toRT and formohydrazide (120 mg, 2.0 mmol) and HOAc (0.5 mL) were added.The resulting reaction was stirred at 85° C. for another 16 h under N₂.The mixture was concentrated. The crude product was purified byPrep-HPLC to give1-((8-(4H-1,2,4-triazol-4-yl)imidazo[1,2-b]pyridazin-2-yl)methyl)-N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(13.5 mg, yield: 14%) as a white solid. ESI-MS [M+H]⁺: 493.1. Purity:100.0% (214 nm), 98.2% (254 nm). ¹H NMR (400 MHz, DMSO): δ 9.66 (s, 2H),8.73 (s, 3H), 8.57 (s, 1H), 8.43 (s, 1H), 8.20 (s, 1H), 7.78 (s, 1H),6.75 (s, 1H), 5.88 (s, 2H), 4.70 (s, 2H).

Example 295

Synthesis ofN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(pyrrolidin-1-ylmethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide

A mixture ofN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((8-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(50 mg, 0.097 mmol), pyrrolidine (8.5 mg, 0.117 mmol), and Cs₂CO₃ (126mg, 0.388 mmol) in DMF (5 mL) was stirred at 25° C. for 16 h. Water (50mL) was added and the mixture was extracted with EtOAc (50 mL×3). Thecombined organic layers were concentrated and purified by prep-HPLC togiveN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(pyrrolidin-1-ylmethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(12 mg, yield: 22.6%) as a white solid. ESI-MS [M+H]⁺: 548.2. Purity:5.14% 214 m), 95.15% (254 nm). ¹H NMR (400 MHz, DMSO): δ 8.69 (t, J=5.5,1H), 8.53 (s, 1H), 8.44 (d, J=2.4, 1H), 8.23-8.18 (m, 2H), 7.79 (s, 1H),6.99 (s, 1H), 6.81-6.70 (m, 1H), 5.72 (s, 2H), 4.68 (t, J=9.1, 2H), 3.84(s, 2H), 2.49 (d, J=1.6, 4H), 2.00-1.88 (m, 1H), 1.70 (d, J=3.2, 4H),0.95-0.87 (m, 2H), 0.68-0.57 (m, 2H).

Example 296

Synthesis of Methyl 3-aminopyridazine-4-carboxylate

To a mixture of 3-aminopyridazine-4-carboxylic acid (5.0 g, 36.0 mmol)in methanol (50 mL) was added H₂SO₄ (5 mL) slowly. The reaction washeated to reflux and stirred at 90° C. for 14 h. The mixture wasconcentrated. The residue was partitioned between EtOAc (200 mL) andsaturated aqueous Na₂CO₃ (200 mL). The aqueous layer was extracted withEtOAc (200 mL×3). The combined organic layers were washed with brine,dried over Na₂SO₄, and concentrated in vacuo to give methyl3-aminopyridazine-4-carboxylate as a yellow solid (4.0 g, yield: 73%).ESI-MS [M+H]⁺: 154.2.

Synthesis of (3-aminopyridazin-4-yl)methanol

To a solution of methyl 3-aminopyridazine-4-carboxylate (4 g, 26.0 mmol)in dry THF (50 mL) was added LiAlH4 (60 mL, 1 M solution in THF, 60mmol) at 0° C. dropwise. The reaction was stirred at 0° C. for 2 h. Thereaction was quenched with Na₂SO₄ 10H₂0, filtered, and washed with EtOAc(100 mL×3). The filtrate was concentrated to give(3-aminopyridazin-4-yl)methanol (1.2 g, yield: 37%) as a yellow solid.ESI-MS [M+H]⁺: 126.2.

Synthesis of (2-(chloromethyl)imidazo[1,2-b]pyridazin-8-yl)methanol

To a solution of (3-aminopyridazin-4-yl)methanol (1.2 g, 9.6 mmol) inEtOAc (50 mL) was added 1,3-dichloropropan-2-one (1.45 g, 11.5 mmol).The reaction was stirred at 90° C. for 16 h. The mixture reaction wasquenched with saturated aqueous NaHCO₃ (70 mL) and extracted with EtOAc(70 mL×3). The combined organic layers were washed with brine, driedover Na₂SO₄, and concentrated to give the crude product which waspurified by silica gel chromatography (PE/EtOAc=1/2) to give(3-aminopyridazin-4-yl)methanol (1.0 g, yield: 53%) as a yellow solid.ESI-MS [M+H]⁺: 198.1.

Synthesis of (2-(azidomethyl)imidazo[1,2-b]pyridazin-8-yl)methanol

To a solution of (3-aminopyridazin-4-yl)methanol (1.0 g, 5.04 mmol) inDMF (10 mL) was added NaN₃ (689 mg, 10.6 mmol) at 0° C. The reactionmixture was stirred at RT for 4 h. Water (100 mL) was added, and themixture was extracted with EtOAc (100 mL×3). The combined organic layerswere washed with brine, dried over Na₂SO₄, and concentrated in vacuo togive crude product which was purified by silica gel chromatography(PE/EtOAc=1/1) to give(2-(azidomethyl)imidazo[1,2-b]pyridazin-8-yl)methanol (400 mg, yield:38.6%) as a yellow solid. ESI-MS [M+H]⁺: 205.2.

Synthesis of Ethyl1-((8-(hydroxymethyl)imidazo[1,2-b]pyridazin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate

To a solution of (2-(azidomethyl)imidazo[1,2-b]pyridazin-8-yl)methanol(400 mg, 1.96 mmol) in t-BuOH (15 mL) and water (5 mL) was added ethylpropiolate (254 mg, 2.6 mmol), CuSO₄ (63 mg, 0.4 mmoL), and sodiumascorbate (79 mg, 0.4 mmoL). The reaction mixture was stirred at RT for3 h. The reaction mixture was poured into H₂O (50 mL) and extracted withEtOAc (100 mL×3). The combined organic layers were washed with brine,dried over Na₂SO₄ and concentrated to give ethyl1-((8-(hydroxymethyl)imidazo[1,2-b]pyridazin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(590 mg, yield: 100%) as a yellow solid which was used in next stepdirectly. ESI-MS [M+H]⁺: 303.1.

Synthesis Ethyl1-((8-(chloromethyl)imidazo[1,2-b]pyridazin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate

To a solution of ethyl1-((8-(hydroxymethyl)imidazo[1,2-b]pyridazin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(604 mg, 2 mmol) in dry DCM (30 mL) was added SOCl₂ (8 mL). Afterstirring at RT for 2 h, the mixture was quenched with saturated aqueousNaHCO₃ (100 mL) and extracted with DCM (100 mL×3). The combined organiclayers were washed with brine, dried over Na₂SO₄, and concentrated togive ethyl1-((8-(chloromethyl)imidazo[1,2-b]pyridazin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(450 mg, yield: 70%) as a yellow solid which was used in next stepdirectly. ESI-MS [M+H]⁺: 321.1.

Synthesis of((2-((4-(ethoxycarbonyl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-b]pyridazin-8-yl)methyl)triphenylphosphonium

A solution of ethyl1-((8-(chloromethyl)imidazo[1,2-b]pyridazin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(450 mg, 1.4 mmol) and triphenylphosphine (1.1 g, 4.2 mmol) in drytoluene (25 mL) was stirred at 110° C. for 48 h. The mixture wasconcentrated to give the crude product which was triturated with PE (100mL), then filtered to give((2-((4-(ethoxycarbonyl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-b]pyridazin-8-yl)methyl)triphenylphosphonium(540 mg, yield: 66%) as a black solid which was used directly in thenext step. ESI-MS [M+H]⁺: 547.2.

Synthesis of Ethyl1-((8-(oxetan-3-ylidenemethyl)imidazo[1,2-b]pyridazin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate

To a solution of((2-((4-(ethoxycarbonyl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-b]pyridazin-8-yl)methyl)triphenylphosphonium(582 mg, 1 mmol) in dry DMF (15 mL) was added NaH (60 mg, 60% in oil,1.5 mmol). The reaction was stirred at 0° C. for 30 min, thenoxetan-3-one (720 mg, 10 mmol) was added. The reaction was stirred at60° C. for another 16 h. The reaction was quenched with NH₄Cl solution(50 mL) and extracted with EtOAc (100 mL×3). The combined organic layerswere washed with brine, dried over Na₂SO₄, and concentrated in vacuo togive the crude product which was purified by silica gel chromatography(DCM/MeOH=10/1) to give ethyl1-((8-(oxetan-3-ylidenemethyl)imidazo[1,2-b]pyridazin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(300 mg, yield: 88%) as a yellow solid. ESI-MS [M+H]⁺: 341.2.

Synthesis of Ethyl1-((8-(oxetan-3-ylmethyl)imidazo[1,2-b]pyridazin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate

To a solution of ethyl1-((8-(oxetan-3-ylidenemethyl)imidazo[1,2-b]pyridazin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(150 mg, 0.44 mmol) in dry MeOH (8 mL) was added CuCl (65 mg, 0.66 mmol)and NaBH₄ (94 mg, 2.46 mmol) at 0° C. After stirring at RT for 3 h, thereaction was quenched with saturated aqueous NH₄Cl solution (30 mL) andextracted with EtOAc (100 mL×3). The combined organic layers were washedwith brine, dried over Na₂SO₄, and concentrated in vacuo to give thecrude product which was purified by silica gel chromatography(DCM/MeOH=20/1) to give ethyl1-((8-(oxetan-3-ylmethyl)imidazo[1,2-b]pyridazin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(25 mg, yield: 16.6%) as a white solid. ESI-MS [M+H]⁺: 343.1.

Synthesis of1-((8-(oxetan-3-ylmethyl)imidazo[1,2-b]pyridazin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicAcid

A solution of 1-(2-(chloromethyl)-3-fluoro-4-methoxyphenyl)-1H-tetrazole(25 mg, 0.07 mmol) and LiOH.H2O (5.7 mg, 0.14 mmol) in THF/H₂O (5 mL/5mL) was stirred at RT for 1 h. The reaction mixture was adjusted to pH 6with hydrochloric acid (0.5 M) and concentrated in vacuo to give1-((8-(oxetan-3-ylmethyl)imidazo[1,2-b]pyridazin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (30 mg, crude, yield: 100%) as a white solid which was used in nextstep without further purification. ESI-MS [M+H]⁺: 315.1.

Synthesis ofN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((8-(oxetan-3-ylmethyl)imidazo[1,2-b]pyridazin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide

To a solution1-((8-(oxetan-3-ylmethyl)imidazo[1,2-b]pyridazin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (30 mg, crude from previous step) in dry DMF (2 mL) was added(2-fluoro-3-methoxy-6-(1H-tetrazol-1-yl)phenyl)methanamine hydrochloride(9.4 mg, 0.04 mmol), HOBT (5.4 mg, 0.04 mmol), EDCI (7.6 mg, 0.04 mmol),and DIPEA (11.61 mg, 0.09 mmol). The reaction mixture was stirred at RTfor 16 h. Water (30 mL) was added, and the mixture was extracted withEtOAc (50 mL×3). The combined organic layers were washed with brine,dried over Na₂SO₄, and concentrated in vacuo to give the crude productwhich was purified by Prep-TLC (DCM/MeOH=20/1) to giveN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((8-(oxetan-3-ylmethyl)imidazo[1,2-b]pyridazin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(6 mg, yield: 30.3%). ESI-MS [M+H]⁺: 496.1. Purity: 88.73% (214 nm),89.50% (254 nm). ¹H NMR (400 MHz, DMSO): δ 8.71 (t, J=5.4 Hz, 1H), 8.59(s, 1H), 8.45 (d, J=2.4 Hz, 1H), 8.41 (d, J=4.6 Hz, 1H), 8.32 (s, 1H),8.21 (d, J=7.4 Hz, 1H), 7.03 (d, J=4.7 Hz, 1H), 6.78-6.75 (m, 1H), 5.80(s, 2H), 4.71 (d, J=5.5 Hz, 2H), 4.67-4.64 (m, 2H), 4.39 (t, J=6.1 Hz,2H), 3.48-3.41 (m, 1H), 3.29 (d, J=7.7 Hz, 2H).

Example 297

Synthesis of1-(imidazo[1,2-a]pyridin-2-ylmethyl)-1H-imidazole-4-carboxylic Acid

To a solution of ethyl1-(imidazo[1,2-a]pyridin-2-ylmethyl)-1H-imidazole-4-carboxylate (120 mg,0.44 mmol) in THF (10 mL) was added LiOH.H₂O (54 mg, 1.33 mmol). Themixture was stirred at RT for 10 h. The reaction mixture was adjusted topH 3-4 with hydrochloric acid (1 M) and then concentrated in vacuo togive 1-(imidazo[1,2-a]pyridin-2-ylmethyl)-1H-imidazole-4-carboxylic acid(177 mg crude) which was used directly in the next step. ESI-MS [M+H]⁺:243.2.

Synthesis ofN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-(imidazo[1,2-a]pyridin-2-ylmethyl)-1H-imidazole-4-carboxamide

To a solution of1-(imidazo[1,2-a]pyridin-2-ylmethyl)-1H-imidazole-4-carboxylic acid (85mg, crude from last step, 0.21 mmol),(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride(73 mg, 0.31 mmol), HOBT (57 mg, 0.42 mmol), EDCI (81 mg, 0.42 mmol) inDMF (5 mL) was added DIPEA (136 mg, 1.05 mmol). The resulting mixturewas stirred at RT for 12 h under N₂. The reaction was quenched withwater (50 mL) and extracted with EtOAc (30 mL×3). The combined organiclayers were washed with brine, dried over Na₂SO₄, and concentrated invacuo to give the crude product which was triturated with DCM (25 mL) togiveN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-(imidazo[1,2-a]pyridin-2-ylmethyl)-1H-imidazole-4-carboxamideas a white solid (20 mg, 23%). ESI-MS [M+H]⁺: 424.1. Purity: 96.72% (214nm), 98.28% (254 nm). ¹H NMR (400 MHz, DMSO): δ 8.56-8.47 (m, 1H), 8.45(d, J=2.5 Hz, 1H), 8.20 (d, J=7.4 Hz, 1H), 8.01 (t, J=5.5 Hz, 1H), 7.85(s, 1H), 7.81 (d, J=1.2 Hz, 1H), 7.72 (d, J=1.2 Hz, 1H), 7.55-7.45 (m,1H), 7.30-7.17 (m, 1H), 6.95-6.81 (m, 1H), 6.81-6.68 (m, 1H), 5.34 (s,2H), 4.67 (d, J=5.5 Hz, 2H).

Example 298

Synthesis of1-((6-cyclopropyl-8-(hydroxymethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicAcid

A solution of tert-butyl1-((6-cyclopropyl-8-(hydroxymethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(1 g, 2.71 mmol) in DCM/TFA (20 mL/4 mL) was stirred at 25° C. for 3 h.The reaction was concentrated in vacuo to give1-((6-cyclopropyl-8-(hydroxymethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (800 mg) as a brown solid which was used in next step directly.ESI-MS [M+H]⁺: 314.1.

Synthesis ofN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(hydroxymethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide

To a solution of1-((6-cyclopropyl-8-(hydroxymethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (800 mg, crude from previous step),(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride(897 mg, 3.82 mmol), and HATU (1.45 g, 3.82 mmol) in DMF (10 mL) wasadded DIPEA (2.3 g, 17.85 mmol). The resulting mixture was stirred at25° C. for 16 h. Water (100 mL) was added, and the mixture was extractedwith EtOAc (50 mL×3). The combined organic layers were concentrated togive the crude product which was purified by silica gel chromatography(MeOH/DCM=1/50) to giveN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(hydroxymethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(700 mg, yield: 52%) as a white solid. ESI-MS [M+H]⁺: 495.1.

Synthesis ofN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((8-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide

To a solution ofN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(hydroxymethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(700 mg, 1.42 mmol) in dry DCM (10 mL) was added SOCl₂ (3 mL) at 0° C.The reaction mixture was stirred at 0° C. for 3 h. The mixture wasconcentrated to give the crude product which was purified by silica gelchromatography (MeOH/DCM=1/50) to giveN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((8-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(500 mg, yield: 68.7%) as a yellow solid. ESI-MS [M+H]⁺: 514.1.

Synthesis of1-((8-(aminomethyl)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-1,2,3-triazole-4-carboxamide

A solution ofN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((8-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(50 mg, 0.097 mmol) in NH₃ (5 mL, 2 M solution in i-PrOH) in a sealedtube was stirred at 70° C. for 16 h. The reaction mixture wasconcentrated to give the crude product which purified by Prep-HPLC togive1-(3-(aminomethyl)phenyl)-N-(5-(3-cyclopropyl-1-hydroxypropyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-1,2,4-triazole-5-carboxamide(20 mg, yield: 41.7%) as a white solid. ESI-MS [M+H]⁺: 494.1. Purity:98.52% (214 nm), 99.24% (254 nm). ¹H NMR (400 MHz, DMSO): δ 8.70 (t,J=5.3 Hz, 1H), 8.55 (s, 1H), 8.44 (d, J=2.4 Hz, 1H), 8.33 (s, 1H), 8.26(s, 1H), 8.20 (d, J=7.4 Hz, 1H), 7.83 (s, 1H), 7.03 (s, 1H), 6.79-6.73(m, 1H), 5.73 (s, 2H), 4.70 (d, J=5.5 Hz, 2H), 4.01 (s, 2H), 1.94-1.89(m, 1H), 0.95-0.90 (m, 2H), 0.71-0.65 (m, 2H).

Example 299

Synthesis of tert-butyl1-((8-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate

To a solution of tert-butyl1-((6-cyclopropyl-8-(hydroxymethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(500 mg, 1.355 mmol) in dry DCM (10 mL) was added SOCl₂ (320 mg, 2.7mmol) at 0° C. The mixture was stirred at 25° C. for 3 h. The mixturewas concentrated to give the crude product which was purified by silicagel chromatography (MeOH/DCM=1/50) to give tert-butyl1-((8-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(420 mg, yield: 81%) as a yellow solid. ESI-MS [M+H]⁺: 388.1.

Synthesis of1-((6-cyclopropyl-8-((2-(dimethylamino)ethoxy)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicAcid

To a suspension of NaH (320 mg, 60% suspension in paraffin oil, 8.0mmol) in DMF (5 mL) was added 2-(dimethylamino)ethan-1-ol (144 mg, 1.61mmol) at 0° C. The resulting reaction was stirred at 0° C. for 30 min,then a solution of tert-butyl1-((8-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(418 mg, 1.08 mmol) was added. The reaction mixture was stirred at 25°C. for another 16 h. The reaction was quenched with water (20 mL) andconcentrated in vacuo to give the crude product, which was purified bysilica gel chromatography (MeOH/DCM=1/4) to give1-((6-cyclopropyl-8-((2-(dimethylamino)ethoxy)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (300 mg, yield: 72%) as a yellow solid. ESI-MS [M+H]⁺: 385.1.

Synthesis ofN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-((2-(dimethylamino)ethoxy)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide

A mixture of1-((6-cyclopropyl-8-((2-(dimethylamino)ethoxy)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (30 mg, 0.078 mmol),(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride(22 mg, 0.094 mmol), HATU (44.4 mg, 0.117 mmol), DIPEA (70 mg, 0.54mmol) in DMF (5 mL) was stirred at 25° C. for 16 h. The reaction wasdiluted with water (20 mL) and extracted with EtOAc (30 mL×3). Thecombined organic layers were washed with brine, dried over Na₂SO₄, andconcentrated in vacuo to give the crude product which was purified byPrep-HPLC to giveN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-((2-(dimethylamino)ethoxy)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(2.5 mg, yield: 56%) as a white solid. ESI-MS [M+H]⁺: 567.1. Purity:97.44% (214 nm), 97.03% (254 nm). ¹H NMR (400 MHz, DMSO) δ 8.69 (t,J=5.4 Hz, 1H), 8.53 (s, 1H), 8.44 (d, J=2.4 Hz, 1H), 8.39 (d, J=2.4 Hz,1H), 8.28 (s, 1H), 8.19 (dd, J=9.7, 7.4 Hz, 2H), 7.83 (s, 1H), 7.01 (s,1H), 6.81-6.65 (m, 2H), 5.73 (s, 2H), 4.79-4.61 (m, 4H), 4.47 (s, 2H),3.60 (t, J=5.9 Hz, 2H), 2.44 (t, J=5.8 Hz, 2H), 2.14 (s, 6H), 1.99-1.89(m, 1H), 0.97-0.87 (m, 2H), 0.70-0.59 (m, 2H).

Example 300

Synthesis ofN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(((3,3,3-trifluoro-2-hydroxypropyl)amino)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide

A mixture of1-((8-(aminomethyl)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(200 mg, 0.405 mmol) and 2-(trifluoromethyl)oxirane (20 ml) in a sealedtube was stirred at 120° C. for 8 h. The mixture was concentrated andpurified by Prep-HPLC to giveN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(((3,3,3-trifluoro-2-hydroxypropyl)amino)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(20 mg, yield: 8.1%) as a white solid. ESI-MS [M+H]⁺: 606.1. Purity:97.60% (214 nm), 96.73% (254 nm). ¹H NMR (400 MHz, DMSO): δ 8.69-8.74(m, 1H), 8.54 (s, 1H), 8.44 (d, J=2.2, 1H), 8.25 (s, 1H), 8.20 (d,J=7.4, 1H), 7.80 (s, 1H), 7.00 (s, 1H), 6.76 (t, J=6.9, 1H), 5.73 (s,2H), 4.70 (d, J=5.4, 2H), 4.02-4.06 (m, 2H), 3.90-4.00 (m, 2H),2.72-2.78 (m, 1H), 2.62-2.67 (m, 1H), 1.86-1.97 (m, 1H), 0.88-0.95 (m,2H), 0.64-0.70 (m, 2H).

Example 301

Synthesis of1-((6-cyclopropyl-8-((2,2-diethoxyethoxy)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicAcid

To a mixture of tert-butyl1-((6-cyclopropyl-8-(hydroxymethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate(740 mg, 2.0 mmol) in DMF (10 mL) was added NaH (400 mg, 60%, 10.0 mmol)at 0° C. The mixture was stirred at RT for 1 h and then2-bromo-1,1-diethoxyethane (1.57 g, 8.0 mmol) was added. The reactionmixture was stirred at RT for 18 h. The reaction was quenched withsaturated aqueous NH₄Cl (100 mL), extracted with DCM/MeOH (10/1, 50mL×5), and the combined organic layers were washed with brine, driedover Na₂SO₄ and concentrated in vacuo. The crude product was purified byflash column chromatography (DCM/MeOH=5/1) to give1-((6-cyclopropyl-8-((2,2-diethoxyethoxy)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (300 mg, yield: 35%) as yellow oil. ESI-MS [M+H]⁺: 430.1.

Synthesis ofN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-((2,2-diethoxyethoxy)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide

A mixture of1-((6-cyclopropyl-8-((2,2-diethoxyethoxy)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (120 mg, 0.28 mmol),(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride(99 mg, 0.42 mmol), HOBT (57 mg, 0.42 mmol), EDCI (80 mg, 0.42 mmol) andDIPEA (108 mg, 0.84 mmol) in DMF (5 mL) was stirred at 30° C. for 18 h.The reaction mixture was diluted with water (50 mL) and extracted withEtOAc (45 mL×3). The combined organic layers were washed with brine andconcentrated. The residue was purified by silica gel chromatography(DCM/MeOH=15/1) to affordN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-((2,2-diethoxyethoxy)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(150 mg, yield: 88%) as a yellow solid. ESI-MS [M+H]⁺: 612.1.

Synthesis ofN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-((2-oxoethoxy)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide

A mixture ofN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-((2,2-diethoxyethoxy)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(150 mg, 0.245 mmol) in TFA/H₂O/DCM (0.5 mL/0.5 mL/4 mL) was stirred atRT for 5 h. The reaction was quenched with saturated aqueous NaHCO₃ (10mL) and extracted with DCM (20 mL×3). The combine organic layers werewashed with brine, dried over Na₂SO₄, and concentrated. The residue waspurified by silica gel chromatography (DCM/MeOH=10/1) to affordN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-((2-oxoethoxy)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(120 mg, yield: 91.6%). ESI-MS [M+H]⁺: 537.1.

Synthesis ofN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-((2-hydroxyethoxy)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide

To a mixture ofN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-((2-oxoethoxy)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(120 mg, 0.22 mmol) in MeOH (10 mL) was added NaBH₄ (42 mg, 1.10 mmol)slowly at 0° C. The resulting reaction was stirred at RT for 1 h. Thereaction was quenched with water (20 mL) and extracted with DCM/MeOH(10/1, 50 mL×3). The combined organic layer was washed with brine, driedover Na₂SO₄, and concentrated. The residue was purified by prep-HPLC toaffordN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-((2-hydroxyethoxy)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(12 mg, yield: 10%) as a white solid. ESI-MS [M+H]⁺: 539.2. Purity:98.97% (214 nm), 99.65% (254 nm). ¹H NMR (400 MHz, DMSO): δ 8.76 (t,J=5.3 Hz, 1H), 8.66 (d, J=7.2 Hz, 1H), 8.57 (s, 1H), 8.47 (d, J=2.3 Hz,1H), 8.21 (d, J=7.4 Hz, 1H), 8.15 (s, 1H), 7.54 (s, 1H), 6.77 (t, J=6.9Hz, 1H), 5.93 (d, J=5.9 Hz, 2H), 4.79 (s, 2H), 4.71 (d, J=5.4 Hz, 2H),3.56 (s, 4H), 2.05 (s, 1H), 1.06-0.98 (m, 2H), 0.80-0.73 (m, 2H).

Example 302

Synthesis of1-((8-((2-((tert-butylsulfinyl)amino)ethoxy)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-1,2,3-triazole-4-carboxamide

A mixture ofN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-((2-oxoethoxy)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(110 mg, 0.21 mmol), 2-methylpropane-2-sulfinamide (38 mg, 0.31 mmol),and CuSO₄ (66 mg, 0.41 mmol) in MeOH (3 mL) was stirred at RT for 18 h.NaBH₄ (23 mg, 0.61 mmol) was added and the reaction mixture was stirredat RT for another 1 h. The reaction was quenched with saturated NH₄Clsolution (50 mL) and extracted with DCM/MeOH (10/1, 50 mL×5). Thecombined organic layers were washed with brine, dried over Na₂SO₄ andconcentrated in vacuo. The crude product was purified by silica gelchromatography (DCM/MeOH=10/1) to give1-((8-((2-((tert-butylsulfinyl)amino)ethoxy)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(100 mg, yield: 74%) as a yellow solid. ESI-MS [M+H]⁺: 643.1.

Synthesis of1-((8-((2-aminoethoxy)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-1,2,3-triazole-4-carboxamide

A mixture of1-((8-((2-((tert-butylsulfinyl)amino)ethoxy)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(100 mg, 0.16 mmol) in HCl/MeOH (4 mL, 4 M solution in MeOH, 16 mmol)was stirred at RT for 4 h. The reaction mixture was concentrated and theresidue was purified by prep-HPLC to afford1-((8-((2-aminoethoxy)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(16 mg, yield: 19%) as a white solid. ESI-MS [M+H]⁺: 538.2. Purity:99.02% (214 nm), 100.00% (254 nm). ¹H NMR (400 MHz, DMSO): δ 8.72 (t,J=5.2 Hz, 1H), 8.56 (s, 1H), 8.44 (d, J=1.9 Hz, 1H), 8.31 (s, 1H), 8.21(d, J=7.4 Hz, 1H), 7.86 (s, 1H), 7.08 (s, 1H), 6.76 (t, J=6.9 Hz, 1H),5.74 (s, 2H), 4.83-4.62 (m, 4H), 3.65 (s, 2H), 2.95 (s, 2H), 2.00-1.87(m, 1H), 0.98-0.88 (m, 2H), 0.73-0.64 (m, 2H).

Example 303

Synthesis ofN-((7-bromoimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide

To a solution of1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (100 mg, 0.35 mmol), (7-bromoimidazo[1,5-a]pyridin-1-yl)methanaminehydrochloride (110 mg, 0.41 mmol), HOBT (67 mg, 0.49 mmol) and EDCI (94mg, 0.49 mmol) in DMF (5 mL) was added DIPEA (226 mg, 1.75 mmol). Theresulting mixture was stirred at RT for 4 h. The reaction was pouredinto H₂O (50 mL) and a white solid precipitated out. The mixture wasfiltered, and the filter cake was washed with H₂O (100 mL) and dried togiveN-((7-bromoimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(30 mg, yield: 17.5%) as a white solid. ESI-MS [M+H]⁺: 491.0. Purity:97.57% (214 nm), 98.57 (254 nm). ¹H NMR (400 MHz, DMSO): δ 8.91 (t,J=5.8 Hz, 1H), 8.56 (s, 1H), 8.34 (s, 1H), 8.31 (s, 1H), 8.24 (d, J=7.4Hz, 1H), 8.01 (s, 1H), 7.82 (s, 1H), 7.40 (d, J=9.3 Hz, 1H), 7.00 (dd,J=9.4, 1.5 Hz, 1H), 6.72 (dd, J=7.4, 1.8 Hz, 1H), 5.72 (s, 2H), 4.61 (d,J=5.9 Hz, 2H), 1.95-1.89 (m, J=13.4, 8.4, 5.1 Hz, 1H), 0.94-0.89 (m,2H), 0.69-0.65 (m, 2H).

Example 304

Inhibitory Activity of Exemplary Compounds Against Plasma Kallikrein.

Example compounds were evaluated for inhibition of the human activatedkallikrein enzyme in two formats of an assay employing a fluorogenicpeptide substrate. In one assay format, the concentrations of reagentswere as follows: 20 mM Tris pH 7.5, 1 mM EDTA, 150 mM sodium chloride,0.1% PEG-400, 0.1% Triton X-100, 500 pM activated kallikrein enzyme, 300uM Pro-Phe-Arg-7-amido-4-methylcoumarin substrate. Prior to reactioninitiation with substrate, enzyme and inhibitors were preincubated for30 min at RT. After initiation with substrate, reactions were incubatedfor 10 min at RT and fluorescence emission at 460 nm from 380 nmexcitation measured with a microplate reader. In another assay format,the concentrations of reagents were as follows: 20 mM Tris pH 7.5, 1 mMEDTA, 150 mM sodium chloride, 0.1% PEG-400, 0.1% Triton X-100, 5 pMactivated kallikrein enzyme, 300 uM Pro-Phe-Arg-7-amido-4-methylcoumarinsubstrate. Prior to reaction initiation with substrate, enzyme andinhibitors were preincubated for 30 min at RT. After initiation withsubstrate, reactions were incubated for 18 h at RT and fluorescenceemission at 460 nm from 380 nm excitation measured with a microplatereader.

Table 1 provides the results of the assay in the format with 500 pMactivated kallikrein assay. For the compounds listed in Table 1, theEC₅₀ values are reported according to the following ranges: A≤1.0 nM;1.0 nM<B≤10 nM; 10 nM<C≤100 nM; 100 nM<D≤2000 nM; 2000 nM<E.

TABLE 1 Primary Dose Response Compound Assay: Average EC50 I-1 C I-2 AI-3 C I-4 B I-5 A I-6 B I-7 B I-8 A I-9 C I-10 A I-11 B I-12 C I-13 AI-14 A I-15 A I-16 B I-17 B I-18 B I-19 B I-20 B I-21 B I-22 D I-23 AI-24 B I-25 B I-26 B I-27 B I-28 B I-29 C I-30 B I-31 A I-32 C I-33 CI-34 C I-35 D I-36 C I-37 C I-38 B I-39 B I-40 A I-41 C I-42 C I-43 AI-44 A I-45 B I-46 C I-47 B I-48 D I-49 C I-50 A I-51 A I-52 A I-53 DI-54 C I-55 C I-56 B I-57 A I-58 B I-59 A I-60 A I-61 B I-62 D I-63 CI-64 B I-65 A I-66 A I-67 C I-68 A I-69 D I-70 C I-71 A I-72 B I-73 AI-74 B I-75 A I-76 A I-77 C I-78 A I-79 B I-80 A I-81 A I-82 C I-83 CI-84 C I-85 A I-86 A I-87 A I-88 B I-89 D I-90 A I-91 C I-92 A I-93 AI-94 C I-95 B I-96 E I-97 A I-98 A I-99 A I-100a A I-100b A I-100c AI-101 A I-102 A I-103 A I-104a A I-104b A I-105 A I-106 A I-107 A I-108A I-109 A I-110 A I-111 A I-112 A I-113 B I-114 A I-115 A I-116 B I-117A I-118 B I-119 A I-120 A I-121 A I-122 A I-123 B I-124 B I-125 A I-126A I-127 A I-128 A I-129 A I-130 C I-131 A I-132 A I-133 A I-134 A I-135A I-136 A I-137 A I-138 A I-139 A I-140 A I-141 A I-142 B I-143 A I-144A I-145 A I-146 A I-147 A I-148 A I-149 A I-150 A I-151 C I-152 A I-153A I-154 A I-155 A I-156 A I-157a A I-157b A I-158 A I-159 A I-160 BI-161 B I-162 A I-163a A I-163b A I-164 A I-165 A I-166a A I-166b AI-167 A I-168 A I-169 A I-170 A I-171 A I-172 A I-173 A I-174 A I-175 AI-176 B I-177 B I-178 C I-179 A I-180 A I-181 A I-182 A I-183 A I-184 AI-185 A I-186 A I-187 A I-188 B I-189 A I-190 A I-191 B I-192 A I-193 AI-194 A I-195 D I-196 B I-197 D I-198 A I-199 A I-200 A I-201 A I-202 AI-203 A I-204 A I-205 A I-206 A I-207 A I-208 A I-209 B I-210a A I-210bA I-211 C I-212 A I-213 A I-214 A I-215 A I-216 A I-217 B I-218 B I-219C I-220 A I-221a A I-221b A I-221c C I-222 D I-223 A I-224a A I-224b AI-225 A I-226 A I-227a C I-227b D I-228 A I-229 C I-230 A I-231 A I-232C I-233 B I-234 C I-235 D I-236 C I-237 A I-238 A I-239 B I-240 A I-241aA I-241b A I-242 A I-243 B I-244 C I-245a A I-245b A I-246 A I-247 AI-248 A I-249 A I-250 A I-251a B I-251b A I-252 C I-253 A I-254 B I-255A I-256 B I-257 A I-258 A I-259 B I-260 A I-261 A I-262 A I-263 A I-264A I-265a A I-265b A I-266 A I-267 A I-268 B I-269 B I-270a B I-270b AI-271 A I-272 A I-273 B I-274 D I-275 C I-276 A I-277 C I-278 D I-279 AI-280 C I-281 A I-282 D I-283 A I-284 C I-285 C I-286 C I-287 D I-288 AI-289 A I-290 C I-291 C I-292 C I-293 C I-294 C I-295 A I-296 C I-297 CI-298 A I-299 A I-300 A I-301 A I-302 A I-303 A

Example 305

Comparative Inhibitory Activity of Various Compounds Against PlasmaKallikrein

Table 2 provides comparative plasma kallikrein inhibition potency in theassay format with 500 pM activated kallikrein assay (described in detailin the preceding example). For the compounds listed in Table 1, the EC₅₀values are reported according to the following ranges: A≤1.0 nM; 1.0nM<B≤10 nM; 10 nM<C≤100 nM; 100 nM<D≤2000 nM; 2000 nM<E.

TABLE II Primary Dose Response Assay: Compound Average EC50

C

B

C

B

C

C

D

D

D

Example 306

Synthesis of 4-chloro-3-fluoropicolinaldehyde

To a solution of 2, 2, 6, 6-tetramethylpiperidine (35.4 g, 250.88 mmol)in 200 mL THF was added n-Butyllithium (2.4 M in hexane, 100 mL, 240mmol) dropwise at 0° C. The reaction mixture was cooled to −78° C. afterstirring at 0° C. for 1 h and a solution of 4-chloro-3-fluoropyridine(30.0 g, 228.08 mmol) in THF (100 mL) was added dropwise. The resultingreaction mixture was stirred at −78° C. for 2 h, a solution of DMF (17.5g, 239.48 mmol) in THF (50 mL) was added dropwise, and the resultingreaction mixture was stirred at −78° C. for another 1 h. The reactionwas quenched with H₂O (50 mL), and extracted with ethyl acetate (200mL×3). The combined organic layers were washed with brine, dried overwith anhydrous magnesium sulphate, filtered, and concentrated. Theresidue was purified by silica gel column chromatography (petroleumether/ethyl acetate=3/1) to afford 4-chloro-3-fluoropicolinaldehyde(26.0 g, yield: 71%). ESI-MS [M+H]⁺: 160.1.

Synthesis ofN-((4-chloro-3-fluoropyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide

To a solution of 4-chloro-3-fluoropicolinaldehyde (26.0 g, mixture,163.0 mmol) in DCM (100 mL) was added cesium carbonate (96.0 g, 293.3mmol) and 2-methylpropane-2-sulfinamide (19.8 g, 163.0 mmol) at RT. Thereaction mixture was stirred for 3 h at RT. After the reaction wascomplete, the reaction mixture was filtrated and washed with DCM threetimes. To the combined mixture was added MeOH (40 mL), and then theresulting mixture was cooled to 0° C. by ice-water bath. Sodiumborohydride (15.5 g, 409.0 mmol) was added slowly in portions. Thereaction mixture was warmed up to RT and stirred at this temperature for2 h. The reaction was quenched with H₂O carefully. The resulting mixturewas extracted with DCM (100 mL×3), the combined organic solvent wasdried by sodium sulfate, filtered, and concentrated to get crudeN-((4-chloro-3-fluoropyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide(43.3 g, crude) as yellow solid. ESI-MS [M+H]⁺: 265.1.

Synthesis of (4-chloro-3-fluoropyridin-2-yl)methanamine hydrochloride

To a solution ofN-((4-chloro-3-fluoropyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide(about 162.4 mmol) in ethyl acetate (100 mL) was added a solution ofhydrochloride acid in ethyl acetate (3 M, 200 mL). The resultingreaction mixture was stirred at RT for 3 h. After the reaction wascompleted, the reaction mixture was filtered to give the crude product,which was washed with ethyl acetate and dried in vacuum to afford(4-chloro-3-fluoropyridin-2-yl)methanamine hydrochloride (25.0 g, 78%,mixture) as a pink solid. ¹H NMR (400 MHz, DMSO) δ 8.75 (br, 3H), 8.47(d, J=5.2 Hz, 1H), 7.80 (t, J=5.6 Hz, 1H), 4.28-4.26 (m, 2H).

Synthesis of N-((4-chloro-3-fluoropyridin-2-yl)methyl)formamide

To a solution of (4-chloro-3-fluoropyridin-2-yl)methanaminehydrochloride (25.0 g, mixture, 127.0 mmol) in THF (200 mL) was addedtriethylamine (38.5 g, 380.6 mmol) and ethyl formate (100 mL) at RT. Theresulting reaction mixture was stirred at 70° C. overnight. After thereaction was complete, the reaction mixture was filtered, the solid waswashed with DCM three times. The combined organic solvent was washedwith brine, dried by sodium sulfate, filtrated, and concentrated toafford N-((4-chloro-3-fluoropyridin-2-yl)methyl)formamide (crude), whichwas used in the next step directly without purification. ESI-MS [M+H]⁺:189.1.

Synthesis of 7-chloro-8-fluoroimidazo[1,5-a]pyridine

To a solution of N-((4-chloro-3-fluoropyridin-2-yl)methyl)formamide(crude, about 126.89 mmol) in dry acetonitrile (200 mL) was addedphosphoryl trichloride (18 mL, 1.5 eq), and the resulting reactionmixture was stirred at reflux for 3 h. After the reaction was completed,the reaction mixture was cooled down to RT, and then poured into H₂O(200 mL) carefully. The pH was adjusted to 8 with saturated sodiumbicarbonate, and then the resulting mixture was extracted with ethylacetate (200 mL×3). The combined organic phase was washed with brine,dried over sodium sulphate, filtrated, and concentrated in vacuo. Theresidue was purified by silica gel chromatography (ethyl acetate) toafford 7-chloroimidazo[1,5-a]pyridine (12.0 g, yield: 56%) as a whitesolid. ESI-MS [M+H]⁺: 171.1.

Synthesis of 7-chloro-8-fluoroimidazo[1,5-a]pyridine-1-carbaldehyde

A solution of 7-chloro-8-fluoroimidazo[1,5-a]pyridine (9.0 g, 52.6 mmol)in dry DMF (12 mL) was cooled with an ice-water bath to 0-5° C.Phosphorus oxychloride (7.4 g, 78.9 mmol, 1.5 eq) was added dropwise,and then the reaction mixture was stirred at 100° C. for 2 h. After thereaction was completed, the reaction mixture was cooled down to RT andpoured into saturated sodium bicarbonate aqueous (200 mL) carefully. Theresulting mixture was stirred at RT for 2 h and extracted with ethylacetate (3×200 mL). The combined organic phase was washed with brine,dried over sodium sulphate, filtered, and concentrated in vacuo. Theresidue was purified by recrystallization (petroleum ether/ethylacetate=1/1) to afford 7-chloroimidazo[1,5-a]pyridine-1-carbaldehyde(5.2 g, yield: 47%) as a brown solid. ESI-MS [M+H]⁺: 181.1.

Synthesis of(Z)—N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methylene)-2-methylpropane-2-sulfinamide

To a solution of 7-chloro-8-fluoroimidazo[1,5-a]pyridine-1-carbaldehyde(5.2 g, 26.19 mmol) and 2-methylpropane-2-sulfinamide (3.2 g, 26.71mmol) in THF (200 mL) was added tetraethoxytitanium (15.0 g, 65.50 mol).The reaction mixture was stirred at reflux overnight. After the reactionwas completed, the reaction mixture was concentrated and the residue waspurified by column chromatography (ethyl acetate) to give(E)-N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methylene)-2-methylpropane-2-sulfinamide(7.77 g, 98%) as a white solid. ESI-MS [M+H]⁺: 302.1.

Synthesis ofN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-2-methylpropane-2-sulfinamide

To a solution of(E)-N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methylene)-2-methylpropane-2-sulfinamide(7.77 g, 25.75 mmol) in MeOH (200 mL) was added sodium borohydride (2.44g, 64.37 mmol) slowly. The resulting reaction mixture was stirred at RTfor 3 h. After the reaction was completed, the reaction was quenchedwith H₂O (50 mL). The resulting mixture was extracted with ethyl acetate(200 mL×3), the combined organic phase was washed with brine, dried overanhydrous sodium sulphate, filtered, and concentrated in vacuum toaffordN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-2-methylpropane-2-sulfinamide(7.77 g, 99%) as a white solid. ESI-MS [M+H]⁺: 304.1.

Synthesis of (7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanaminehydrochloride

A mixture ofN-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-2-methylpropane-2-sulfinamide(7.77 g, 25.5 mmol) and hydrochloride acid in ethyl acetate (3 M, 100mL) was stirred at RT for 2 h, and then the reaction mixture wasfiltered to give the crude product, which was washed with ethyl acetateand dried in vacuum to afford(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloridesalt (6.03 g, quant.) as a white solid. ESI-MS [M-NH₂]⁺: 182.9. ¹H NMR(400 MHz, DMSO): δ 8.64 (d, J=2.0 Hz, 1H), 8.44 (br, 3H), 8.33 (d, J=7.2Hz, 1H), 6.92 (t, J=6.8 Hz, 1H), 4.26-4.22 (m, 2H).

Example 307

Synthesis of (4-chloropyridin-2-yl)methyl 4-methylbenzenesulfonate

Sodium hydride (44 g, 60%, 1.096 mol) was added to a cooled (0° C.)solution of (4-chloropyridin-2-yl)methanol (80 g, 548 mmol) in THF (1500mL) at 0° C. The mixture was stirred at 0° C. for 1 h, and tosylchloride (104 g, 548 mmol) was added. After stirring at 0° C. foranother 3 h, the mixture was quenched with H₂O (50 mL), and extractedwith ethyl acetate (120 mL×3), the combined organic layers were washedwith brine, dried over with anhydrous magnesium sulphate, filtered, andconcentrated to afford (4-chloropyridin-2-yl)methyl4-methylbenzenesulfonate (162 g, crude) as a brown oil which was used inthe next step without purification. ESI-MS [M+H]⁺: 296.1.

Synthesis of N-((4-chloropyridin-2-yl)methyl)-N-formylformamide

To a solution of (4-bromopyridin-2-yl)methyl 4-methylbenzenesulfonate(crude, 162 g, 548 mmol) in DMF (500 mL) was added sodium diformamide(52 g, 548 mmol) at RT. The mixture was stirred for 3 h and concentratedin vacuum. The residue was washed with ethyl acetate three times. Thecombined filtrate was concentrated and the crude product was purified bysilica gel column chromatography (petroleum ether/ethyl acetate=1/1) toafford N-((4-chloropyridin-2-yl)methyl)-N-formylformamide (100 g, yield:83%). ESI-MS [M+H]⁺: 198.1.

Synthesis of N-((4-chloropyridin-2-yl)methyl)formamide

To a solution of N-((4-chloropyridin-2-yl)methyl)-N-formylformamide (100g, 465 mmol) in MeOH (100 mL) was added H₂O (8.4 g, 465 mol) and formicacid (55.7 g, 929 mmol) at RT. The mixture was stirred at 60° C.overnight and then concentrated to affordN-((4-chloropyridin-2-yl)methyl)formamide (crude) which was used in thenext step without purification. ESI-MS [M+H]⁺: 171.1.

Synthesis of 7-chloroimidazo[1,5-a]pyridine

To a solution of N-((4-chloropyridin-2-yl)methyl)formamide (crude, about465 mmol) in dry acetonitrile (300 mL) was added phosphorus oxybromide(100 mL, 1.5 eq) and the reaction mixture was stirred at reflux for 2 h.After cooling down, the mixture was poured onto H₂O (200 mL). The pH ofthe mixture was adjusted to 8 with saturated sodium bicarbonate and thenextracted with ethyl acetate (200 mL×3). The combined organic phaseswere washed with brine and dried over sodium sulphate, filtered andconcentrated in vacuo. The residue was purified by silica gelchromatography (ethyl acetate) to afford 7-chloroimidazo[1,5-a]pyridine(59 g, yield: 71%) as a yellow solid. ESI-MS [M+H]⁺: 153.1.

Synthesis of 7-chloroimidazo[1,5-a]pyridine-1-carbaldehyde

A solution of 7-chloroimoimidazo[1,5-a]pyridine (47 g, 307 mmol) in dryDMF (26.9 g, 368 mmol) was cooled in an ice bath to 0-5° C. Phosphorusoxychloride (56.4 g, 368 mmol, 1.2 eq) was added dropwise at 0-5° C. andthe reaction mixture was subsequently stirred at 100° C. for 2 h. Thereaction mixture is cooled and poured onto saturated aqueous sodiumbicarbonate (200 mL) and kept stirring for another 2 h and extractedwith ethyl acetate (3×200 mL). The combined organic phases were washedwith brine and dried over sodium sulphate, filtered, and concentrated invacuo. The residue was purified by silica gel chromatography (petroleumether/ethyl acetate=1/1) to afford7-chloroimidazo[1,5-a]pyridine-1-carbaldehyde (32 g, yield: 58%) as ayellow solid. ESI-MS [M+H]⁺: 181.1.

Synthesis of(Z)—N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methylene)-2-methylpropane-2-sulfinamide

To a solution of 7-chloroimidazo[1,5-a]pyridine-1-carbaldehyde (22 g,121 mmol) and 2-methylpropane-2-sulfinamide (14.7 g, 121 mmol) in THF(500 mL) was added tetraethoxytitanium (Ti(OEt)₄) (55 g, 243 mol). Themixture was stirred at reflux overnight. The mixture was concentratedand the residues purified by column chromatography (ethyl acetate) togive(Z)—N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methylene)-2-methylpropane-2-sulfinamide(32 g, quant.) as a yellow solid. ESI-MS [M+H]⁺: 284.1.

Synthesis ofN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-2-methylpropane-2-sulfinamide

To a solution of(Z)—N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methylene)-2-methylpropane-2-sulfinamide(32 g, 121.67 mmol) in MeOH (200 mL), was added sodium borohydride (13.5g, 365 mmol) slowly. The mixture was stirred at RT for 3 h andconcentrated. The residue was diluted with 50 mL H₂O and extracted withethyl acetate (200 mL×3). After washing with brine, the combined organiclayers were dried over anhydrous sodium sulphate, filtered, andconcentrated in vacuum to affordN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-2-methylpropane-2-sulfinamide(32.3 g, quant.) as a white solid. ESI-MS [M+H]⁺: 286.1.

Synthesis of (7-chloroimidazo[1,5-a]pyridin-1-yl)methanaminehydrochloride

A mixture ofN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-2-methylpropane-2-sulfinamide(33.73 g, 117.6 mmol) and hydrochloride in ethyl acetate (3 M, 100 mL)was stirred at RT for 2 h and then filter to give the crude productwhich was washed with ethyl acetate and dried in vacuum to afford (27.33g, quant.) as a white solid. ESI-MS [M-NH₂]⁺: 164.9. Purity: 98.7%. ¹HNMR (400 MHz, DMSO) δ 8.91 (s, 1H), 8.58 (br, 3H), 8.52 (d, J=7.6 Hz,1H), 8.18 (dd, J=0.8 Hz, 1H), 6.93 (dd, J=2.0, 7.6 Hz, 1H), 4.34 (q,J=5.6 Hz, 2H).

Example 308

Synthesis of 7-iodoimidazo[1,5-a]pyridine

To a solution of 7-bromoimidazo[1,5-a]pyridine (2.8 g, 14.2 mmol) in atube were added copper(I) iodide (270 mg, 1.42 mmol), sodium iodide(10.7 g, 71.1 mmol), N¹,N²-dimethylcyclohexane-1,2-diamine (404 mg, 2.84mmol) and 1,4-dioxane (15 mL). The mixture was stirred at 100° C. for 16h. The mixture was diluted with H₂O (100 mL), extracted with ethylacetate (30 mL×3). The combined organic layers were washed with brine,dried, evaporated and purified by silica gel chromatography (petroleumether/ethyl acetate=1/1) to afford 7-iodoimidazo[1,5-a]pyridine (2.7 g,yield: 77%) as a yellow solid. ESI-MS [M+H]⁺: 245.0.

Synthesis of 7-iodoimidazo[1,5-a]pyridine-1-carbaldehyde

A solution of 7-iodoimidazo[1,5-a]pyridine (2.45 g, 10 mmol) in dry DMF(3 mL) was cooled in an ice bath to 0° C. Phosphorus oxychloride (2.3 g,15 mmol, 1.5 eq) was added dropwise at 0° C. and the reaction mixture issubsequently stirred at 100° C. over 1.5 h. After cooling down, thesolvent was removed and the pH of the mixture was adjusted to 8 withaqueous saturated sodium bicarbonate and then extracted with ethylacetate (50 mL×3). The combined organic phases were dried over sodiumsulphate, filtered, and concentrated in vacuo. The residue was purifiedby silica gel chromatography (petroleum ether/ethyl acetate=1/1) toafford 7-iodoimidazo[1,5-a]pyridine-1-carbaldehyde (1.1 g, yield: 40%)as a yellow solid. ESI-MS [M+H]⁺: 273.0.

Synthesis ofN-boryl-N-((7-iodoimidazo[1,5-a]pyridin-1-yl)methyl)-2-methylpropane-2-sulfinamide

A mixture of 7-iodoimidazo[1,5-a]pyridine-1-carbaldehyde (1.1 g, 4.04mmol) in THF (50 mL) was added 2-methylpropane-2-sulfinamide (592 mg,4.85 mmol) and tetraethoxytitanium (Ti(OEt)₄, 1.84 g, 8.09 mmol). Themixture was stirred at reflux for 4 h. After cooling down, sodiumborohydride (615 mg, 16.18 mmol) was added slowly and the mixture wasstirred at RT for 8 h. 30 mL of H₂O was added to the mixture, extractedwith ethyl acetate (30 mL×3). The combined organic layers were driedover anhydrous sodium sulphate, filtered and concentrated in vacuum. Theresidue was purified by silica gel chromatography (petroleum ether:ethylacetate=1:1) to affordN-boryl-N-((7-iodoimidazo[1,5-a]pyridin-1-yl)methyl)-2-methylpropane-2-sulfinamide(950 mg, yield: 60%) as a white solid. ESI-MS [M+H]⁺: 390.0.

Synthesis of (7-iodoimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride

A mixture ofN-boryl-N-((7-iodoimidazo[1,5-a]pyridin-1-yl)methyl)-2-methylpropane-2-sulfinamide(950 mg, 2.44 mmol) and hydrochloride in Ethyl acetate (3M, 20 mL) wasstirred at RT for 4 h and then filtered to give the crude product whichwas washed with ethyl acetate and dried in vacuum to afford(7-iodoimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride (757 mg,quant.) as a white solid. ESI-MS [M-NH₂]⁺: 256.9. Purity: 97.9%. ¹H NMR(400 MHz, DMSO) δ 8.79 (s, 1H), 8.45 (br, 3H), 8.43 (s, 1H), 8.26 (d,J=7.2 Hz, 1H), 7.03 (d, J=7.6 Hz, 1H), 4.31 (q, J=5.6 Hz, 2H).

Example 309

Synthesis of 7-cyclopropylimidazo[1,5-a]pyridine-1-carbaldehyde

A mixture of 7-bromoimidazo[1,5-a]pyridine-1-carbaldehyde (1.4 g, 6.22mmol), cyclopropylboronic acid (5.4 g, 62.2 mmol), palladium diacetate(100 mg, 0.6 mmol), tricyclohexyl phosphine (200 mg, 06 mmol) andpotassium phosphate (2.7 g, 12.4 mmol) in toluene/H₂O (30 mL, 10/1) wasstirred at reflux overnight. The mixture was concentrated to yield thecrude product, which was purified by flash chromatography (petroleumether/ethyl acetate=1/1) to give7-cyclopropylimidazo[1,5-a]pyridine-1-carbaldehyde (750 mg, yield: 64%)as a brown solid. ESI-MS [M+H]⁺: 187.1.

Synthesis ofN-((7-cyclopropylimidazo[1,5-a]pyridin-1-yl)methyl)-2-methylpropane-2-sulfinamide

To a solution of 7-cyclopropylimidazo[1,5-a]pyridine-1-carbaldehyde (720mg, 3.87 mmol) and 2-methylpropane-2-sulfinamide (710 mg, 5.86 mmol) inTHF (10 mL) was added titanium ethoxide (2.7 g, 11.61 mmol). The mixturewas stirred at reflux overnight. After the reaction was completed,sodium borohydride (580 mg 11.5 mmol) was added, stirred for another 3h. Then the mixture was diluted with H₂O (100 mL), and extracted withethyl acetate (100 mL×3). The combined organic layers were dried andconcentrated. The residue was purified by silica column chromatography(petroleum ether/ethyl acetate=1/1) to giveN-((7-cyclopropylimidazo[1,5-a]pyridin-1-yl)methyl)-2-methylpropane-2-sulfinamide(700 mg, yield: 62%) as a yellow solid.

Synthesis of (7-cyclopropylimidazo[1,5-a]pyridin-1-yl)methanamine

To a solution ofN-((7-cyclopropylimidazo[1,5-a]pyridin-1-yl)methyl)-2-methylpropane-2-sulfinamide(650 mg, 2.14 mmol) in ethyl acetate (20 mL) was added hydrochloride inethyl acetate (3 M, 10 mL). The mixture was stirred at RT for 3 h andthen filtered to give the crude product which was washed with ethylacetate and dried in vacuum to afford(7-cyclopropylimidazo[1,5-a]pyridin-1-yl)methanamine (500 mg, quant.) asa white solid. ESI-MS [M-NH₂]⁺: 171.1. Purity: 92.4%. ¹H NMR (400 MHz,DMSO) δ 9.36 (s, 1H), 8.81 (br, 3H), 8.48 (d, J=7.2 Hz, 1H), 7.81 (s,1H), 6.87 (dd, J=7.2, 1.6 Hz, 1H), 4.42 (q, J=5.6 Hz, 2H), 2.00-1.94 (m,1H), 1.05-1.00 (m, 2H), 0.87-0.85 (m, 2H).

Example 310

Synthesis of 7-ethylimidazo[1,5-a]pyridine-1-carbaldehyde

A mixture of 7-bromoimidazo[1,5-a]pyridine-1-carbaldehyde (2.5 g, 11.11mmol), ethylboronic acid (8.2 g, 111.1 mmol), potassium carbonate (3.2g, 22.2 mmol), and[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (880 mg, 1.2mmol) in 1,4-dioxane (20 mL) was heated to reflux overnight. The mixturewas diluted with H₂O (50 mL) and extracted with ethyl acetate (100mL×3). The combined organic layers were dried and concentrated. Thecrude product was purified with flash chromatography (petroleumether/ethyl acetate=1/1) to give7-ethylimidazo[1,5-a]pyridine-1-carbaldehyde (1.2 g, yield: 62%) as ayellow solid. ESI-MS [M+H]⁺: 175.2.

Synthesis ofN-((7-ethylimidazo[1,5-a]pyridin-1-yl)methyl)-2-methylpropane-2-sulfinamide

To a solution of 7-ethylimidazo[1,5-a]pyridine-1-carbaldehyde (1.2 g,6.89 mmol) and 2-methylpropane-2-sulfinamide (880 mg, 7.23 mmol) in THF(10 mL) was added tetraethoxytitanium (Ti(OEt)₄) (7.9 g, 34.4 mmol). Themixture was stirred at reflux overnight. After cooling down, sodiumborohydride (1.05 g, 27.5 mmol) was added, and the mixture was stirredat RT for another 3 h. Then the mixture was diluted with H₂O (50 mL),and extracted with ethyl acetate (50 mL×3). The combined organic layerswere washed with brine, dried, and concentrated to giveN-((7-ethylimidazo[1,5-a]pyridin-1-yl)methyl)-2-methylpropane-2-sulfinamide(1.4 g, yield: 73%) as a white solid. ESI-MS [M+H]⁺: 280.1.

Synthesis of (7-ethylimidazo[1,5-a]pyridin-1-yl)methanamine

To a solution ofN-((7-ethylimidazo[1,5-a]pyridin-1-yl)methyl)-2-methylpropane-2-sulfinamide(1.4 g, 5.0 mmol) in ethyl acetate (10 mL) was added hydrochloride inethyl acetate (3 M, 10 mL). The mixture was stirred at RT for 3 h andthen filtered to give the crude product which was washed with ethylacetate and dried in vacuum to afford(7-ethylimidazo[1,5-a]pyridin-1-yl)methanamine (1.0 g, quant.) as awhite solid. ESI-MS [M-NH₂]⁺: 159.0. Purity: 97.4%. ¹H NMR (400 MHz,DMSO) δ 9.36 (s, 1H), 8.78 (br, 3H), 8.51 (d, J=4.0 Hz, 1H), 7.87 (s,1H), 6.99 (d, J=4.0 Hz, 1H), 4.45-4.43 (m, 2H), 2.59 (q, J=7.6 Hz, 2H),1.24 (t, J=7.6 Hz, 3H).

Example 311

Synthesis of (5-bromopyridin-2-yl)methanamine

To a solution of 5-bromopicolinonitrile (15 g, 81.96 mol) was added aborane THF complex solution (107 mL, 1 M). The mixture was stirred atambient temperature overnight. The reaction was quenched with MeOH (50mL), stirred at RT for 1 h, and then concentrated to give(5-bromopyridin-2-yl)methanamine (crude) as a brown oil which was usedin the next step without purification. ESI-MS [M+H]⁺: 188.1.

Synthesis of N-((5-bromopyridin-2-yl)methyl)formamide

A solution of (5-bromopyridin-2-yl)methanamine (crude) in formic acid(150 mL) was stirred at 100° C. for 3 h, and then concentrated to giveN-((5-bromopyridin-2-yl)methyl)formamide (crude) as a brown oil whichwas used in the next step without purification. ESI-MS [M+H]⁺: 216.1.

Synthesis of 6-bromoimidazo[1,5-a]pyridine

A solution of N-((5-bromopyridin-2-yl)methyl)formamide (crude) inphosphorus oxychloride (50 mL) was heated to 100° C. for 3 h. Phosphorusoxychloride was removed in vacuum. The residue was poured intoice-water. The pH of the mixture was adjusted to 8 with aqueoussaturated sodium bicarbonate and then extracted with ethyl acetate (200mL×3). The combined organic phases were washed with brine and dried oversodium sulphate, filtered, and concentrated in vacuum. The residue waspurified by silica gel chromatography (petroleum ether/ethylacetate=1/1) to afford 6-bromoimidazo[1,5-a]pyridine (1.2 g, yield:7.4%) as a yellow solid. ESI-MS [M+H]⁺: 198.1.

Synthesis of 6-bromoimidazo[1,5-a]pyridine-1-carbaldehyde

A solution of 6-bromoimidazo[1,5-a]pyridine (1.7 g, 8.63 mmol) in dryDMF (944 mg, 12.9 mmol) was cooled in an ice bath to 0-5° C. Phosphorusoxychloride (1.98 g, 12.9 mmol, 1.5 eq) was added dropwise at 0-5° C.and the reaction mixture was subsequently stirred at 100° C. over 2 h.The reaction mixture was cooled and poured onto aqueous saturated sodiumbicarbonate (200 mL), kept stirring for another 2 h, and extracted withethyl acetate (50 mL×3). The combined organic phases were washed withbrine and dried over sodium sulphate, filtered, and concentrated invacuo. The residue was purified by silica gel chromatography (petroleumether/ethyl acetate=1/1) to afford6-bromoimidazo[1,5-a]pyridine-1-carbaldehyde (500 mg, yield: 26%) as ayellow solid. ESI-MS [M+H]⁺: 226.0.

Synthesis of tert-butyl (1-formylimidazo[1,5-a]pyridin-6-yl)carbamate

To a solution of 6-bromoimidazo[1,5-a]pyridine-1-carbaldehyde (860 mg,3.82 mmol) in dioxane (50 mL), was addedtris(dibenzylideneacetone)dipalladium (Pd₂(dba)₃, 696 mg, 0.76 mmol),Xantphos (440 mg, 0.76 mmol), cesium carbonate (3 g, 9.51 mmol),tert-butyl carbamate (2.22 g, 9.0 mmol). The mixture was stirred atreflux overnight and concentrated. The residue was purified by columnchromatography (ethyl acetate) to giveN-((7-bromoimidazo[1,5-a]pyridin-1-yl)methylene)-2-methylpropane-2-sulfinamide(800 mg, yield: 80%) as a yellow solid. ESI-MS [M+H]⁺: 262.0.

Synthesis of tert-butyl(1-((1,1-dimethylethylsulfinamido)methyl)imidazo[1,5-a]pyridin-6-yl)carbamate

To a solution of tert-butyl(1-formylimidazo[1,5-a]pyridin-6-yl)carbamate (800 mg, 3 mmol) in THF(50 mL), was added 2-methylpropane-2-sulfinamide (370 mg, 3 mmol),tetraethoxytitanium (2.1 g, 9.2 mmol). The mixture was stirred at refluxovernight. After cooling down, sodium borohydride (348 mg, 9.2 mmol) wasadded slowly. The mixture was stirred at RT for 3 h. The mixture wasconcentrated and the residue was purified by column chromatography(petroleum ether/ethyl acetate=100/0 to 90/10) to afford tert-butyl(1-((1,1-dimethylethylsulfinamido)methyl)imidazo[1,5-a]pyridin-6-yl)carbamate(600 mg, yield: 54%) as a white solid. ESI-MS [M+BH₂]⁺: 379.1.

Synthesis of 1-(aminomethyl)imidazo[1,5-a]pyridin-6-amine

To a solution oftert-butyl(1-((1,1-dimethylethylsulfinamido)methyl)imidazo[1,5-a]pyridin-6-yl)carbamate(600 mg, 1.63 mmol) in ethyl acetate (3 mL) was added hydrochloride inethyl acetate (3 M, 2 mL). The mixture was stirred at RT for 3 h andthen filtered to give the crude product which was washed with ethylacetate and dried in vacuum to afford1-(aminomethyl)imidazo[1,5-a]pyridin-6-amine hydrochloride (343 g,yield: 89%) as a white solid. ESI-MS [M-NH₂]⁺: 146. Purity: 99.0%. ¹HNMR (400 MHz, DMSO) δ 9.29 (s, 1H), 8.78 (br, 3H), 8.00 (s, 1H), 7.79(dd, J=10 Hz, 1H), 7.70 (br, 3H), 7.79 (dd, J=10 Hz, 2 Hz, 1H), 4.41 (d,J=5.6 Hz, 2H).

Example 312

Synthesis of7-((trimethylsilyl)ethynyl)imidazo[1,5-a]pyridine-1-carbaldehyde

To a solution of 7-bromoimidazo[1,5-a]pyridine-1-carbaldehyde (660 mg,2.93 mmol), trimethylsilylacetylene (350 mg, 3.52 mmol) in DMF (10 mL)was added cuprous iodide (60 mg, 0.3 mmol),bis(triphenylphosphine)palladium(II) chloride (210 mg, 0.3 mmol) andtriethylamine (600 mg, 5.86 mmol). The mixture was stirred at 100° C.for 2 h. After the reaction was completed, the mixture was diluted withH₂O (20 mL), and extracted with ethyl acetate (50 mL×3). The combinedorganic layers were wash with brine, dried, and concentrated. Theresidue was purified with flash chromatography (petroleum ether/ethylacetate=1/1) to give7-((trimethylsilyl)ethynyl)imidazo[1,5-a]pyridine-1-carbaldehyde (430mg, yield: 45%) as a yellow solid. ESI-MS [M+H]⁺: 243.2.

Synthesis of2-methyl-N-((7-((trimethylsilyl)ethynyl)imidazo[1,5-a]pyridin-1-yl)methyl)propane-2-sulfinamide

To a solution of7-((trimethylsilyl)ethynyl)imidazo[1,5-a]pyridine-1-carbaldehyde (430mg, 1.77 mmol) and 2-methylpropane-2-sulfinamide (230 mg, 1.90 mmol) inTHF (10 mL) was added titanium ethoxide (800 mg, 3.54 mmol). The mixturewas stirred at reflux overnight. After cooling down, sodium borohydride(270 mg, 7.08 mmol) was added, and the mixture was stirred for another 3h. After the reaction was completed, the mixture was diluted with H₂O(50 mL), and extracted with ethyl acetate (50 mL×3). The combinedorganic layers were dried and concentrated to give2-methyl-N-((7-((trimethylsilyl)ethynyl)imidazo[1,5-a]pyridin-1-yl)methyl)propane-2-sulfinamide(500 mg, yield: 81%) as a yellow solid. ESI-MS [M+H]⁺: 348.2.

Synthesis ofN-((7-ethynylimidazo[1,5-a]pyridin-1-yl)methyl)-2-methylpropane-2-sulfinamide

To a solution of2-methyl-N-((7-((trimethylsilyl)ethynyl)imidazo[1,5-a]pyridin-1-yl)methyl)propane-2-sulfinamide(500 mg, 1.44 mmol) in DCM/MeOH (5/1, 6 mL) was added potassiumhydroxide (162 mg, 2.88 mmol). The mixture was stirred at RT for 2 h,then diluted with H₂O (10 mL), and extracted with DCM (20 mL×3). Thecombined organic layers were washed with brine, dried, and concentratedto giveN-((7-ethynylimidazo[1,5-a]pyridin-1-yl)methyl)-2-methylpropane-2-sulfinamide(380 mg crude, yield: 95%) which was used in the next step withoutfurther purification. ESI-MS [M+H]⁺: 276.1.

Synthesis of (7-ethynylimidazo[1,5-a]pyridin-1-yl)methanamine

To a solution ofN-((7-ethynylimidazo[1,5-a]pyridin-1-yl)methyl)-2-methylpropane-2-sulfinamide(380 mg, 1.32 mmol) in ethyl acetate (5 mL) was added hydrochloride inethyl acetate (3 M, 10 mL). The mixture was stirred at RT for 3 h andthen filtered to give the crude product which was washed with ethylacetate and dried in vacuum to afford(7-ethynylimidazo[1,5-a]pyridin-1-yl)methanamine (270 mg, quant.) as ayellow solid. ESI-MS [M-NH₂]⁺: 154.9. Purity: 99.1%. H NMR (400 MHz,DMSO) δ 8.99 (s, 1H), 8.63 (br, 3H), 8.47 (d, J=7.2 Hz, 1H), 8.22 (s,1H), 8.86-8.84 (dd, J=3.6 Hz, 6.0 Hz, 1H), 4.48 (s, 1H), 4.37 (q, J=5.6Hz, 2H).

Example 313

Synthesis of (4-bromopyridin-2-yl)methanol

A solution of methyl 4-bromopicolinate (30 g, 0.139 mol) in EtOH (150mL) was cooled to 0° C. using ice-water bath. Sodium borohydride (11.61g, 0.306 mol) was added slowly into the solution at 0° C. The resultingmixture was stirred at RT for 18 h and then quenched with acetone (50mL). The resulting mixture was stirred for another 1 h. After removingthe solvent, the residue was diluted with H₂O (100 mL) and extractedwith ethyl acetate (200 mL×3). The combined organic layers were driedover anhydrous sodium sulfate, filtered, and concentrated to afford(4-bromopyridin-2-yl)methanol (24.4 g, crude) as a colorless oil. ESI-MS[M+H]⁺: 188.0.

Synthesis of (4-bromopyridin-2-yl)methyl 4-methylbenzenesulfonate

A solution of (4-bromopyridin-2-yl)methanol (24.46 g, 0.13 mol) in THF(300 mL) was added sodium hydride (7.29 g, 0.183 mol, 60%) at 0° C. Theresulting mixture was stirred at 0° C. for 1 h, and tosyl chloride(25.97 g, 0.137 mol) was added. After stirring for another 3 h, thereaction mixture was quenched with H₂O (50 mL), and extracted with ethylacetate (120 mL×3), the combined organic layers were washed with brine,dried over anhydrous magnesium sulfate, filtered, and concentrated toafford (4-bromopyridin-2-yl)methyl 4-methylbenzenesulfonate (44.5 g,crude) as a brown oil, which was used directly in the next step withoutpurification. ESI-MS [M+H]⁺: 344.0.

Synthesis of N-((4-bromopyridin-2-yl)methyl)-N-formylformamide

To a solution of (4-bromopyridin-2-yl)methyl 4-methylbenzenesulfonate(44.5 g, crude, 0.13 mol) in DMF (100 mL) was added sodium diformamide(14.41 g, 0.136 mmol, 1.05 eq) at RT. The resulting reaction mixture wasstirred for 3 h and concentrated in vacuum. The residue was washed withethyl acetate three times. The combined organic layers were concentratedand the crude product was purified by silica gel column chromatography(petroleum ether/ethyl acetate=1/1) to affordN-((4-bromopyridin-2-yl)methyl)formamide (23.7 g, 70%). ESI-MS [M+H]⁺:244.1.

Synthesis of N-((4-bromopyridin-2-yl)methyl)formamide

To a solution of N-((4-bromopyridin-2-yl)methyl)formamide (17.6 g, 72.43mmol) in MeOH (100 mL) was added H₂O (1.30 g, 72.43 mol) and formic acid(6.66 g, 144.86 mmol). The resulting mixture was stirred at 60° C.overnight, and then concentrated to affordN-((4-bromopyridin-2-yl)methyl)formamide (14.7 g, crude). ESI-MS [M+H]⁺:217.0.

Synthesis of 7-bromoimidazo[1,5-a]pyridine

To a solution of N-((4-bromopyridin-2-yl)methyl)formamide (10.0 g, 46.5mmol) in dry acetonitrile (200 mL) was added phosphorus oxybromide (20g, 69.75 mmol, 1.5 eq) and the resulting mixture was stirred at refluxfor 2 h. After the reaction was complete, the reaction mixture wascooled down to RT and poured into H₂O (200 mL). The pH of the solutionwas adjusted to 8 with saturated aqueous sodium bicarbonate. Thesolution was extracted with ethyl acetate (200 mL×3). The combinedorganic phases were washed with brine and dried over sodium sulfate,filtered, and concentrated in vacuo to afford a residue. This residuewas purified by silica gel chromatography (ethyl acetate) to afford7-bromoimidazo[1,5-a]pyridine (7.5 g, 82%) as a yellow solid. ESI-MS[M+H]⁺: 197.0.

Synthesis of 7-bromoimidazo[1,5-a]pyridine-1-carbaldehyde

A solution of 7-bromoimidazo[1,5-a]pyridine (7.5 g, 38.1 mmol) in dryDMF (10 mL) was cooled with ice bath to 0-5° C. Phosphorus oxychloride(8.76 g, 57.1 mmol, 1.5 eq) was added dropwise at this temperature, andthen the reaction mixture was subsequently stirred at 100° C. for 2 h.After the reaction was completed, the reaction mixture was cooled to RTand poured into saturated aqueous sodium bicarbonate (200 mL) and keptstirring for another 2 h. The solution was extracted with ethyl acetate(200 mL×3). The combined organic phases were washed with brine, driedover sodium sulfate, filtered, and concentrated in vacuum to afford aresidue which was purified by silica gel chromatography (petroleumether/ethyl acetate=1/1) to afford7-bromoimidazo[1,5-a]pyridine-1-carbaldehyde (5.5 g, 64%) as a yellowsolid. ESI-MS [M+H]⁺: 224.9.

Synthesis of(E)-N-((7-bromoimidazo[1,5-a]pyridin-1-yl)methylene)-2-methylpropane-2-sulfinamide

To a solution of 7-bromoimidazo[1,5-a]pyridine-1-carbaldehyde (4.3 g,19.1 mmol) and 2-methylpropane-2-sulfinamide (2.36 g, 19.49 mmol) in THF(50 mL) was added titanium ethoxide (8.7 g, 38.21 mmol). The resultingmixture was stirred at reflux overnight. After the reaction wascompletion, the mixture was concentrated and the residue was purified bycolumn chromatography (ethyl acetate) to give(E)-N-((7-bromoimidazo[1,5-a]pyridin-1-yl)methylene)-2-methylpropane-2-sulfinamide(5.7 g, 91%) as a yellow solid. ESI-MS [M+H]⁺: 327.9.

Synthesis ofN-((7-bromoimidazo[1,5-a]pyridin-1-yl)methylene)-2-methylpropane-2-sulfinamide

To a solution ofN-((7-bromoimidazo[1,5-a]pyridin-1-yl)methylene)-2-methylpropane-2-sulfinamide(5.7 g, 17.26 mmol) in MeOH (50 mL) was added sodium borohydride (1.97g, 51.78 mmol) slowly. The resulting mixture was stirred at RT for 3 h.The mixture was concentrated to afford a residue, which was diluted with50 mL H₂O and extracted with ethyl acetate (200 mL×2). After washingwith brine, the combined organic layers were dried over anhydrous sodiumsulfate, filtered, and concentrated in vacuum to affordN-((7-bromoimidazo[1,5-a]pyridin-1-yl)methylene)-2-methylpropane-2-sulfinamide(5.6 g, 98%) as a white solid. ESI-MS [M+H]⁺: 330.0.

Synthesis of (7-bromoimidazo[1,5-a]pyridin-1-yl)methanaminehydrochloride acid salt

To a solution ofN-((7-bromoimidazo[1,5-a]pyridin-1-yl)methylene)-2-methylpropane-2-sulfinamide(5.6 g, 16.96 mmol) in ethyl acetate (30 mL) was added the solution ofhydrochloride in ethyl acetate (3 M, 20 mL). The resulting mixture wasstirred at RT for 3 h and then filtered to give the crude product, whichwas washed with ethyl acetate and dried in vacuum to afford(7-bromoimidazo[1,5-a]pyridin-1-yl)methanaminehydrochloride acid salt(3.9 g, quant.) as a white solid. ESI-MS [M-NH₂]⁺: 208.8. Purity: 98.5%.¹H NMR (400 MHz, DMSO) δ 8.99 (s, 1H), 8.62 (br, 3H), 8.46 (d, J=7.2 Hz,1H), 8.37 (s, 1H), 7.02 (dd, J=1.6, 7.2 Hz, 1H), 4.34 (q, J=5.6 Hz, 2H).

Example 314

Synthesis of 3-fluoro-2-methylpyridine 1-oxide

To a solution of 3-fluoro-2-methylpyridine (5 g, 45.05 mmol) in dry DCM(150 mL) was added m-chloroperbenzoic acid (9.3 g, 54.05 mmol). Themixture was stirred at RT for 16 h and the precipitate was filtered off.The filtrate was evaporated to dryness and the residue was purified bysilica gel chromatography (DCM/MeOH=20/1) to give3-fluoro-2-methylpyridine 1-oxide (4.2 g, 73%) as a yellow solid. ESI-MS[M+H]⁺: 128.1.

Synthesis of 3-fluoro-2-methyl-4-nitropyridine 1-oxide

Fuming nitric acid (10 mL) was added dropwise to a solution of2-methyl-3-fluoropyridine-N-oxide (4.2 g, 33.07 mmol) in concentratedsulphuric acid (30 mL) at 0° C. The solution was stirred at RT for 1.5 hand then for 2 h at 100° C. After cooling, the mixture was poured ontoice and extracted with ethyl acetate (50 mL×3). The combined organiclayers were washed with saturated sodium bicarbonate solution. Afterdrying, the extracts were evaporated and purified by silica gelchromatography (DCM/MeOH=20/1) to give2-methyl-3-fluoro-4-nitropyridine-N-oxide (4.6 g, yield: 81%) as ayellow solid. ESI-MS [M+H]⁺: 173.1.

Synthesis of 4-bromo-3-fluoro-2-methylpyridine 1-oxide

To a solution of 2-methyl-3-fluoro-4-nitropyridine-N-oxide (4.4 g, 25.58mmol) in acetic acid (50 mL) was added acetyl bromide (15.7 g, 128mmol). The mixture was stirred at 100° C. overnight and thenconcentrated. The residue was diluted with H₂O (100 mL) and extractedwith ethyl acetate (50 mL×3). The combined organic layers were washedwith saturated sodium bicarbonate solution, brine, dried, evaporated,and then purified by silica gel chromatography (DCM/MeOH=20/1) to afford4-bromo-3-fluoro-2-methylpyridine 1-oxide (4, 3.6 g, yield: 65%) as awhite solid. ESI-MS [M+H]⁺: 206.0, 208.0.

Synthesis of (4-bromo-3-fluoropyridin-2-yl)methanol

A solution of 4-bromo-3-fluoro-2-methylpyridine 1-oxide (3.4 g, 16.5mmol) in acetic anhydride (50 mL) was stirred at 100° C. for 2 h. Afterremoval of the solvent, the residue was dissolved in MeOH (100 mL) andpotassium carbonate (4.6 g, 33 mmol) was added. The mixture was stirredat RT for 2 h. The mixture was diluted with H₂O and extracted with ethylacetate (30 mL×3). The combined organic layers were washed with brine,dried, evaporated, and then purified by silica gel chromatography(petroleum ether/ethyl acetate=1/1) to afford(4-bromo-3-fluoropyridin-2-yl)methanol (1.6 g, yield: 44%) as a yellowsolid. ESI-MS [M+H]⁺: 206.0, 208.0.

Synthesis of (4-bromo-3-fluoropyridin-2-yl)methyl4-methylbenzenesulfonate

To a solution of (4-bromo-3-fluoropyridin-2-yl)methanol (1.4 g, 6.8mmol) in THF (50 mL) was added sodium hydride (326 mg, 8.16 mmol, 60%)in portions at 0° C. The mixture was stirred for 1 h, and tosyl chloride(1.3 g, 6.8 mmol) was added. After stirring at RT for another 3 h, thereaction was quenched with H₂O (50 mL), and the mixture was extractedwith ethyl acetate (20 mL×3). The combined organic layers were washedwith brine, dried over anhydrous magnesium sulphate, filtered, andconcentrated to afford (4-bromo-3-fluoropyridin-2-yl)methyl4-methylbenzenesulfonate (2.4 g, crude) as a yellow oil which was usedin the next step without purification. ESI-MS [M+H]⁺: 360.0.

Synthesis of N-((4-bromo-3-fluoropyridin-2-yl)methyl)-N-formylformamide

To a solution of (4-bromo-3-fluoropyridin-2-yl)methyl4-methylbenzenesulfonate (2.4 g, crude, 6.67 mmol) in DMF (30 mL) wasadded sodium diformamide (950 mg, 10 mmol) at RT. The mixture wasstirred for 3 h and concentrated in vacuum. The residue was washed withethyl acetate three times. The combined filterate was concentrated toafford crude N-((4-bromo-3-fluoropyridin-2-yl)methyl)-N-formylformamide(1.6 g crude, yield: 92%) as yellow oil, which was used in the next stepwithout further purification. ESI-MS [M+H]⁺: 261.0.

Synthesis of N-((4-bromo-3-fluoropyridin-2-yl)methyl)formamide

To a solution ofN-((4-bromo-3-fluoropyridin-2-yl)methyl)-N-formylformamide (1.6 g, 6.15mmol) in MeOH (50 mL) was added H₂O (110 mg, 6.15 mmol) and formic acid(566 mg, 12.3 mmol) added at RT. The mixture was stirred at 60° C.overnight and then concentrated. The residue was purified by silica gelchromatography (ethyl acetate in petroleum ether, 0 to 100%) to affordto afford N-((4-bromo-3-fluoropyridin-2-yl)methyl)formamide (1.1 g,yield: 77%) as an off-white solid. ESI-MS [M+H]⁺: 233.0.

Synthesis of 7-bromo-8-fluoroimidazo[1,5-a]pyridine

To a solution of N-((4-bromo-3-fluoropyridin-2-yl)methyl)formamide (1.1g, 4.72 mmol) in dry acetonitrile (50 mL) was added phosphorusoxybromide (2.03 g, 7.08 mmol). The resulting he reaction mixture wasstirred at reflux for 2 h. After cooling down, the mixture was pouredonto H₂O (200 mL). The pH of the mixture was adjusted to 8 with aqueoussaturated sodium bicarbonate and then extracted with ethyl acetate (30mL×3). The combined organic phases were washed with brine and dried oversodium sulphate, filtered and concentrated in vacuum. The residue waspurified by silica gel chromatography (ethyl acetate) to afford7-bromo-8-fluoroimidazo[1,5-a]pyridine (950 mg, yield: 94%) as a yellowsolid. ESI-MS [M+H]⁺: 215.0.

Synthesis of 7-bromo-8-fluoroimidazo[1,5-a]pyridine-1-carbaldehyde

A solution of 7-bromo-8-fluoroimidazo[1,5-a]pyridine (944 mg, 4.39 mmol)in dry DMF (3 mL) was cooled in an ice bath to 0-5° C. Phosphorusoxychloride (950 mg, 6.62 mmol) was added dropwise at 0-5° C. and thereaction mixture is subsequently stirred at 100° C. over 2 h. Thereaction mixture was cooled and poured onto saturated sodium bicarbonateaqueous (50 mL) and kept stirring for another 2 h and extracted withethyl acetate (30 mL×3). The combined organic phases were washed withbrine and dried over sodium sulphate, filtered, and concentrated invacuum. The residue was purified by silica gel chromatography (petroleumether/ethyl acetate=0 to 100%) to afford7-bromo-8-fluoroimidazo[1,5-a]pyridine-1-carbaldehyde (550 mg, yield:51%) as a yellow solid. ESI-MS [M+H]⁺: 245.0.

Synthesis ofN-((7-bromo-8-fluoroimidazo[1,5-a]pyridin-1-yl)methylene)-2-methylpropane-2-sulfinamide

To a solution of 7-bromo-8-fluoroimidazo[1,5-a]pyridine-1-carbaldehyde(300 mg, 1.24 mmol) and 2-methylpropane-2-sulfinamide (182 mg, 1.49mmol) in THF (30 mL) was added titanium(IV) ethoxide (565 mg, 2.48mmol). The mixture was stirred at reflux overnight. The mixture wasconcentrated and the residue was purified by column chromatography(ethyl acetate) to giveN-((7-bromo-8-fluoroimidazo[1,5-a]pyridin-1-yl)methylene)-2-methylpropane-2-sulfinamide(380 mg, yield: 89%) as a yellow solid. ESI-MS [M+H]⁺: 346.0.

Synthesis ofN-((7-bromo-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-2-methylpropane-2-sulfinamide

To a solution ofN-((7-bromo-8-fluoroimidazo[1,5-a]pyridin-1-yl)methylene)-2-methylpropane-2-sulfinamide(380 mg, 1.1 mmol) in MeOH (30 mL) was added sodium borohydride (126 mg,3.3 mmol) slowly. The mixture was stirred at RT for 3 h. The mixture wasconcentrated and the residues were diluted with 50 mL of H₂O andextracted with ethyl acetate (30 mL×3). The combined organic layers werewashed with brine, dried over anhydrous sodium sulphate, filtered, andconcentrated in vacuum to affordN-((7-bromo-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-2-methylpropane-2-sulfinamide(345 mg, yield: 89%) as a white solid. ESI-MS [M+H]⁺: 348.0.

Synthesis of (7-bromo-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine

To a solution ofN-((7-bromo-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-2-methylpropane-2-sulfinamide(340 mg, 0.98 mmol) in ethyl acetate (20 mL) was added hydrochloride inethyl acetate (3 M, 20 mL). The mixture was stirred at RT for 3 h andthen filtered to give the crude product which was washed with ethylacetate and dried in vacuum to afford(7-bromo-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloridesalt (270 mg, quant.) as a white solid. ESI-MS [M-NH₂]⁺: 227.8. Purity:95.8%. ¹H NMR (400 MHz, DMSO) δ 8.65 (s, 1H), 8.44 (br, 3H), 8.25 (d,J=7.2 Hz, 1H), 6.95 (t, J=6.8 Hz, 1H), 4.24 (q, J=5.6 Hz, 2H).

Example 315

Synthesis of (4-methoxypyridin-2-yl)methyl 4-methylbenzenesulfonate

To a solution of (4-methoxypyridin-2-yl)methanol (10 g, 71.86 mmol) inTHF (300 mL) was added potassium hydroxide (6.05 g, 107.8 mmol) followedby tosyl chloride (16.45 g, 86.24 mmol) at 0° C. the reaction mixturewas warmed to RT with stirring for 12 h, and filtered with Celite. Thefiltrate was concentrated to afford (4-methoxypyridin-2-yl)methyl4-methylbenzenesulfonate (21.0 g, crude) as a yellow oil which was usedin the next step without purification. ESI-MS [M+H]⁺: 294.0.

Synthesis of N-formyl-N-((4-methoxypyridin-2-yl)methyl)formamide

To a solution of (4-methoxypyridin-2-yl)methyl 4-methylbenzenesulfonate(21.0 g, crude, 71.86 mmol) in DMF (300 mL) was added sodium diformamide(8.2 g, 86.23 mmol, 1.2 eq) at RT. The mixture was stirred for 3 h andthe solvent was removed, 50 mL of H₂O was added, and then extracted withethyl acetate (50 mL×6). The combined organic layers were dried overanhydrous magnesium sulphate, filtered, and concentrated to affordN-formyl-N-((4-methoxypyridin-2-yl)methyl)formamide (12.0 g, crude) asbrown oil which was used in the next step without purification. ESI-MS[M+H]⁺: 194.1.

Synthesis of N-((4-methoxypyridin-2-yl)methyl)formamide

To a solution of N-formyl-N-((4-methoxypyridin-2-yl)methyl)formamide (12g, crude, 61.85 mmol) in MeOH (150 mL) was added H₂O (1 mL) and formicacid (3 mL) added at RT. The mixture was stirred at 60° C. overnight andthen concentrated to afford N-((4-methoxypyridin-2-yl)methyl)formamide(10.0 g, crude). ESI-MS [M+H]⁺: 167.0.

Synthesis of 7-methoxyimidazo[1,5-a]pyridine

A mixture of N-((4-methoxypyridin-2-yl)methyl)formamide (10.0 g, 60.2mmol) and phosphoryl trichloride (50 mL) was stirred at 60° C. for 1 h.After cooling down, the solvent was removed and the pH of the mixturewas adjusted to 8 with saturated aqueous sodium bicarbonate and thenextracted with ethyl acetate (100 mL×3). The combined organic phaseswere dried over sodium sulphate, filtered, and concentrated in vacuo.The residue was purified by silica gel chromatography (petroleumether/ethyl acetate=1/1) to afford 7-methoxyimidazo[1,5-a]pyridine (2.37g, yield: 27%) as a yellow oil. ESI-MS [M+H]⁺: 149.0.

Synthesis of 7-methoxyimidazo[1,5-a]pyridine-1-carbaldehyde

A solution of 7-methoxyimidazo[1,5-a]pyridine (2.37 g, 16.02 mmol) indry DMF (10 mL) was cooled in an ice bath to 0° C. Phosphorusoxychloride (3.68 g, 24.02 mmol, 1.5 eq) was added dropwise at 0° C. andthe reaction mixture is subsequently stirred at 100° C. over 1.5 h.After cooling down, the solvent was removed and the pH of the mixturewas adjusted to 8 with saturated sodium bicarbonate aqueous and thenextracted with ethyl acetate (50 mL×3). The combined organic phases weredried over sodium sulphate, filtered and concentrated in vacuo. Theresidue was purified by silica gel chromatography (petroleum ether/ethylacetate=1/1) to afford 7-methoxyimidazo[1,5-a]pyridine-1-carbaldehyde(727 mg, yield: 26%) as a yellow solid. ESI-MS [M+H]⁺: 177.1.

Synthesis ofN-boryl-N-((7-methoxyimidazo[1,5-a]pyridin-1-yl)methyl)-2-methylpropane-2-sulfinamide

To a solution of 7-methoxyimidazo[1,5-a]pyridine-1-carbaldehyde (727 mg,4.13 mmol) in THF (10 mL) was added 2-methylpropane-2-sulfinamide (525mg, 4.34 mmol) and tetraethoxytitanium (Ti(OEt)₄, 2.83 g, 12.391 mmol).The mixture was stirred at reflux for 4 h. After cooling down, sodiumborohydride (471 mg, 12.39 mmol) was added slowly and the mixture wasstirred at RT for 8 h. 30 mL of H₂O was added to the mixture, and themixture was extracted with ethyl acetate (30 mL×3). The combined organiclayers were dried over anhydrous sodium sulphate, filtered andconcentrated in vacuum. The residue was purified by silica gelchromatography (petroleum ether/ethyl acetate=1/1) to affordN-boryl-N-((7-methoxyimidazo[1,5-a]pyridin-1-yl)methyl)-2-methylpropane-2-sulfinamide(1.12 g, yield: 93%) as a yellow solid. ESI-MS [M+H]⁺: 294.1.

Synthesis of (7-methoxyimidazo[1,5-a]pyridin-1-yl)methanamine

A mixture ofN-boryl-N-((7-methoxyimidazo[1,5-a]pyridin-1-yl)methyl)-2-methylpropane-2-sulfinamide(720 mg, 2.45 mmol) and hydrochloride in ethyl acetate (3 M, 10 mL) wasstirred at RT for 4 h and then filtered to give the crude product whichwas washed with ethyl acetate and dried in vacuum to afford(7-methoxyimidazo[1,5-a]pyridin-1-yl)methanamine (500.5 mg, yield: 95%)as a white solid. ESI-MS [M-NH₂]⁺: 161.1. Purity: 97.4%. ¹H NMR (400MHz, DMSO) δ 9.30 (s, 1H), 8.81 (br, 3H), 8.49 (d, J=7.6 Hz, 1H), 7.56(d, J=2.4 Hz, 1H), 6.84 (dd, J=7.6, 2.4 Hz, 1H), 4.41 (q, J=5.6 Hz, 2H),3.88 (s, 3H).

Example 316

Synthesis of tert-butyl((7-bromoimidazo[1,5-a]pyridin-1-yl)methyl)carbamate

To a solution of (7-bromoimidazo[1,5-a]pyridin-1-yl)methanaminehydrochloride salt (2 g, 7.66 mmol) in DCM (30 mL) was addedtriethylamine (4.3 mL, 30.6 mmol) and di-tert-butyl dicarbonate (3.5 mL,15.3 mmol). The mixture was stirred at RT for 2 h. TLC showed that thereaction was completed. The mixture was concentrated, dissolved in ethylacetate, washed with saturated ammonium chloride. The organic layer wasconcentrated, purified by column chromatography (DCM/MeOH=10/1) to givetert-butyl ((7-bromoimidazo[1,5-a]pyridin-1-yl)methyl)carbamate (2 g,yield: 80%) as a yellow oil. ESI-MS [M+H]⁺: 326.1.

Synthesis of tert-butyl((7-cyanoimidazo[1,5-a]pyridin-1-yl)methyl)carbamate

To a solution of tert-butyl((7-bromoimidazo[1,5-a]pyridin-1-yl)methyl)carbamate (200 mg, 0.615mmol) in DMF (3 mL) was added 1,1′-bis(diphenylphosphino)ferrocene (64mg, 0.12 mmol), tris(dibenzylideneacetone)dipalladium (Pd₂(dba)₃, 55 mg,0.06 mmol) and zinc cyanide (144 mg, 1.23 mmol). The mixture was stirredat 150° C. in microwave reactor for 1 h and concentrated. The residuewas purified by column chromatography (DCM/MeOH=10/1) to give tert-butyl((7-cyanoimidazo[1,5-a]pyridin-1-yl)methyl)carbamate (117 mg, yield:70%) as a yellow oil. ESI-MS [M+H]⁺: 273.1.

Synthesis of 1-(aminomethyl)imidazo[1,5-a]pyridine-7-carbonitrile

A mixture of tert-butyl((7-cyanoimidazo[1,5-a]pyridin-1-yl)methyl)carbamate (270 mg, 0.99 mmol)and hydrochloride in ethyl acetate (3 M, 20 mL) was stirred at RT for 2h and then filtered to give the crude product which was washed withethyl acetate and dried in vacuum to afford1-(aminomethyl)imidazo[1,5-a]pyridine-7-carbonitrile (201.3 mg, quant.)as a yellow solid. ESI-MS [M−NH₂]⁺: 156.0. Purity: 96.3%.

1. A compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein: Cy^(A) isselected from 3- to 7-membered saturated or partially unsaturatedmonocyclic heterocyclene having 1-2 heteroatoms selected from oxygen,nitrogen, and sulfur, 5- to 6-membered heteroarylene having 1-4heteroatoms selected from oxygen, nitrogen, and sulfur, 7- to10-membered saturated or partially unsaturated bicyclic heterocyclylenehaving 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur, and7- to 10-membered bicyclic heteroarylene having 1-4 heteroatoms selectedfrom oxygen, nitrogen, and sulfur, wherein Cy^(A) is substituted with0-4 R^(A) groups; each R^(A) is independently selected from halogen,—CN, —C(R)═N(R), —C(O)R, —C(O)₂R, —C(O)N(R)₂, —NO₂, —N(R)—N(R)₂, —N(R)₂,—N(R)C(O)R, —N(R)C(O)₂R, —N(R)C(O)N(R)₂, —N(R)S(O)₂R, —OR, —OC(O)R,—OC(O)N(R)₂, —SR, —S(O)R, —S(O)₂R, —S(O)N(R)₂, —S(O)₂N(R)₂, or anoptionally substituted group selected from C₁₋₆ aliphatic, phenyl, 5- to6-membered heteroaryl having 1-4 heteroatoms selected from oxygen,nitrogen, and sulfur, 3- to 7-membered saturated or partiallyunsaturated monocyclic carbocyclyl, and 3- to 7-membered saturated orpartially unsaturated monocyclic heterocyclyl having 1-2 heteroatomsselected from oxygen, nitrogen, and sulfur; Cy^(B) is selected from 3-to 7-membered saturated or partially unsaturated monocyclic heterocyclylhaving 1-2 heteroatoms selected from oxygen, nitrogen, and sulfur, 5- to6-membered heteroaryl having 1-4 heteroatoms selected from oxygen,nitrogen, and sulfur, 7- to 10-membered saturated or partiallyunsaturated bicyclic heterocyclyl having 1-5 heteroatoms selected fromoxygen, nitrogen, and sulfur, and 7- to 10-membered bicyclic heteroarylhaving 1-5 heteroatoms selected from oxygen, nitrogen, and sulfur,wherein Cy^(B) is substituted with 0-5 R^(B) groups; each R^(B) isindependently selected from halogen, —CN, —C(R)═N(R), —C(O)R, —C(O)₂R,—C(O)N(R)₂, —NO₂, —N(R)—N(R)₂, —N(R)₂, —N(R)C(O)R, —N(R)C(O)₂R,—N(R)C(O)N(R)₂, —N(R)S(O)₂R, —OR, —OC(O)R, —OC(O)N(R)₂, —SR, —S(O)R,—S(O)₂R, —S(O)N(R)₂, —S(O)₂N(R)₂, or an optionally substituted groupselected from C₁₋₆ aliphatic, phenyl, 5- to 6-membered heteroaryl having1-4 heteroatoms selected from oxygen, nitrogen, and sulfur, 3- to7-membered saturated or partially unsaturated monocyclic carbocyclyl,and 3- to 7-membered saturated or partially unsaturated monocyclicheterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, andsulfur; L is selected from -QC(R)₂—, —C(R)₂Q-, -QC(Q)-, —C(Q)Q-,—C(R)₂QC(O)—, and —C(O)QC(R)₂—, wherein each Q is independently amonovalent or divalent group as valency allows, selected from the groupconsisting of O, N(R), and (S); R¹, R², R³, and R⁴ are independentlyselected from hydrogen and C₁₋₆ aliphatic; R⁵, R⁶, R⁷, R⁸, and R⁹ areindependently selected from hydrogen, halogen, —CN, —C(R)═N(R), —C(O)R,—C(O)₂R, —C(O)N(R)₂, —NO₂, —N(R)—N(R)₂, —N(R)₂, —N(R)C(O)R, —N(R)C(O)₂R,—N(R)C(O)N(R)₂, —N(R)S(O)₂R, —OR, —OC(O)R, —OC(O)N(R)₂, —SR, —S(O)R,—S(O)₂R, —S(O)N(R)₂, —S(O)₂N(R)₂, or an optionally substituted groupselected from C₁₋₆ aliphatic, phenyl, 5- to 6-membered heteroaryl having1-4 heteroatoms selected from oxygen, nitrogen, and sulfur, 3- to7-membered saturated or partially unsaturated monocyclic carbocyclyl,and 3- to 7-membered saturated or partially unsaturated monocyclicheterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, andsulfur; and each R is independently hydrogen, —CN, or an optionallysubstituted group selected from C₁₋₆ aliphatic, phenyl, 5- to 6-memberedheteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, andsulfur, 3- to 7-membered saturated or partially unsaturated monocycliccarbocyclyl, and 3- to 7-membered saturated or partially unsaturatedmonocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen,nitrogen, and sulfur; or two R groups on the same carbon or nitrogen aretaken together with their intervening atoms to form a ring selected from3- to 7-membered saturated or partially unsaturated monocyclic ringhaving 0-2 heteroatoms selected from oxygen, nitrogen, and sulfur, and5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen,nitrogen, and sulfur; with the proviso that the compound is other thanN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-2-((3-chloroquinolin-6-yl)methyl)isonicotinamide.2. The compound of claim 1, wherein the compound is of Formula (IV):

or a pharmaceutically acceptable salt thereof, wherein: Cy^(A) is a5-membered heteroarylene having 1-4 heteroatoms selected from oxygen adnitrogen, wherein Cy^(A) is substituted with 0-3 R^(A) groups; L isselected from —NC(O)— and —C(O)N—; R⁶, R⁸, and R⁹ are independentlyselected from hydrogen, halogen, —CN, —C(R)═N(R), —C(O)R, —C(O)₂R,—C(O)N(R)₂, —NO₂, —N(R)—N(R)₂, —N(R)₂, —N(R)C(O)R, —N(R)C(O)₂R,—N(R)C(O)N(R)₂, —N(R)S(O)₂R, —OR, —OC(O)R, —OC(O)N(R)₂, —SR, —S(O)R,—S(O)₂R, —S(O)N(R)₂, —S(O)₂N(R)₂, or an optionally substituted groupselected from C₁₋₆ aliphatic, phenyl, 5- to 6-membered heteroaryl having1-4 heteroatoms selected from oxygen, nitrogen, and sulfur, 3- to7-membered saturated or partially unsaturated monocyclic carbocyclyl,and 3- to 7-membered saturated or partially unsaturated monocyclicheterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, andsulfur; R⁷ is —F, —Cl, or —Br; W⁴ is carbon or nitrogen; R¹⁰ and R¹¹ areeach optionally present, and if present are independently selected fromhalogen, —CN, —C(R)═N(R), —C(O)R, —C(O)₂R, —C(O)N(R)₂, —NO₂,—N(R)—N(R)₂, —N(R)₂, —N(R)C(O)R, —N(R)C(O)₂R, —N(R)C(O)N(R)₂,—N(R)S(O)₂R, —OR, —OC(O)R, —OC(O)N(R)₂, —SR, —S(O)R, —S(O)₂R,—S(O)N(R)₂, —S(O)₂N(R)₂, or an optionally substituted group selectedfrom C₁₋₆ aliphatic, phenyl, 5- to 6-membered heteroaryl having 1-4heteroatoms selected from oxygen, nitrogen, and sulfur, 3- to 7-memberedsaturated or partially unsaturated monocyclic carbocyclyl, and 3- to7-membered saturated or partially unsaturated monocyclic heterocyclylhaving 1-2 heteroatoms selected from oxygen, nitrogen, and sulfur; R¹³is selected from halogen, —CN, —C(R)═N(R), —C(O)R, —C(O)₂R, —C(O)N(R)₂,—NO₂, —N(R)—N(R)₂, —N(R)₂, —N(R)C(O)R, —N(R)C(O)₂R, —N(R)C(O)N(R)₂,—N(R)S(O)₂R, —OR, —OC(O)R, —OC(O)N(R)₂, —SR, —S(O)R, —S(O)₂R,—S(O)N(R)₂, —S(O)₂N(R)₂, or an optionally substituted group selectedfrom C₂₋₆ aliphatic, phenyl, 5- to 6-membered heteroaryl having 1-4heteroatoms selected from oxygen, nitrogen, and sulfur, 3- to 7-memberedsaturated or partially unsaturated monocyclic carbocyclyl, and 3- to7-membered saturated or partially unsaturated monocyclic heterocyclylhaving 1-2 heteroatoms selected from oxygen, nitrogen, and sulfur; R¹⁴is optionally present, and if present and is selected from halogen, —CN,—C(R)═N(R), —C(O)R, —C(O)₂R, —C(O)N(R)₂, —NO₂, —N(R)—N(R)₂, —N(R)C(O)R,—N(R)C(O)₂R, —N(R)C(O)N(R)₂, —N(R)S(O)₂R, —OC(O)R, —OC(O)N(R)₂, —SR,—S(O)R, —S(O)₂R, —S(O)N(R)₂, —S(O)₂N(R)₂, or an optionally substitutedgroup selected from C₃₋₆ aliphatic, phenyl, 5- to 6-membered heteroarylhaving 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur, 3- to7-membered saturated or partially unsaturated monocyclic carbocyclyl,and 3- to 7-membered saturated or partially unsaturated monocyclicheterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, andsulfur; and each R is independently hydrogen, —CN, or an optionallysubstituted group selected from C₁₋₆ aliphatic, phenyl, 5- to 6-memberedheteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, orsulfur, 3- to 7-membered saturated or partially unsaturated monocycliccarbocyclyl, and 3- to 7-membered saturated or partially unsaturatedmonocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen,nitrogen, and sulfur; or two R groups on the same carbon or nitrogen aretaken together with their intervening atoms to form a ring selected from3- to 7-membered saturated or partially unsaturated monocyclic ringhaving 0-2 heteroatoms selected from oxygen, nitrogen, and sulfur, and5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen,nitrogen, and sulfur.
 3. The compound of claim 1, wherein the compoundis of Formula (V):

or a pharmaceutically acceptable salt thereof, wherein: Cy^(A) is a5-membered heteroarylene having 1-4 nitrogens, wherein when Cy^(A)comprises 3 nitrogens, Cy^(A) is not

L is selected from —NC(O)— and —C(O)N—; R⁶, R⁸, and R⁹ are independentlyselected from hydrogen, halogen, —CN, —C(R)═N(R), —C(O)R, —C(O)₂R,—C(O)N(R)₂, —NO₂, —N(R)—N(R)₂, —N(R)₂, —N(R)C(O)R, —N(R)C(O)₂R,—N(R)C(O)N(R)₂, —N(R)S(O)₂R, —OR, —OC(O)R, —OC(O)N(R)₂, —SR, —S(O)R,—S(O)₂R, —S(O)N(R)₂, —S(O)₂N(R)₂, or an optionally substituted groupselected from C₁₋₆ aliphatic, phenyl, 5- to 6-membered heteroaryl having1-4 heteroatoms selected from oxygen, nitrogen, and sulfur, 3- to7-membered saturated or partially unsaturated monocyclic carbocyclyl,and 3- to 7-membered saturated or partially unsaturated monocyclicheterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, andsulfur; R⁷ is —F, —Cl, or —Br; R¹⁰ is optionally present, and if presentis selected from halogen, —CN, —C(R)═N(R), —C(O)R, —C(O)₂R, —C(O)N(R)₂,—NO₂, —N(R)—N(R)₂, —N(R)₂, —N(R)C(O)R, —N(R)C(O)₂R, —N(R)C(O)N(R)₂,—N(R)S(O)₂R, —OR, —OC(O)R, —OC(O)N(R)₂, —SR, —S(O)R, —S(O)₂R,—S(O)N(R)₂, —S(O)₂N(R)₂, or an optionally substituted group selectedfrom C₁₋₆ aliphatic, phenyl, 5- to 6-membered heteroaryl having 1-4heteroatoms selected from oxygen, nitrogen, and sulfur, 3- to 7-memberedsaturated or partially unsaturated monocyclic carbocyclyl, and 3- to7-membered saturated or partially unsaturated monocyclic heterocyclylhaving 1-2 heteroatoms selected from oxygen, nitrogen, and sulfur; R¹¹is optionally present, and if present is selected from halogen, —CN,—C(R)═N(R), —C(O)R, —C(O)N(R)₂, —NO₂, —N(R)—N(R)₂, —N(R)₂, —N(R)C(O)R,—N(R)C(O)₂R, —N(R)C(O)N(R)₂, —N(R)S(O)₂R, —OR, —OC(O)R, —OC(O)N(R)₂,—SR, —S(O)R, —S(O)₂R, —S(O)N(R)₂, —S(O)₂N(R)₂, or an optionallysubstituted group selected from C₁₋₆ aliphatic, phenyl, 5- to 6-memberedheteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, andsulfur, 3- to 7-membered saturated or partially unsaturated monocycliccarbocyclyl, and 3- to 7-membered saturated or partially unsaturatedmonocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen,nitrogen, and sulfur; R¹¹ is selected from —CN, —C(R)═N(R), —C(O)R,—C(O)₂R, —C(O)N(R)₂, —NO₂, —N(R)—N(R)₂, —N(R)₂, —N(R)C(O)R, —N(R)C(O)₂R,—N(R)C(O)N(R)₂, —N(R)S(O)₂R, —OR, —OC(O)R, —OC(O)N(R)₂, —SR, —S(O)R,—S(O)₂R, —S(O)N(R)₂, —S(O)₂N(R)₂, or an optionally substituted groupselected from phenyl, 5- to 6-membered heteroaryl having 1-4 heteroatomsselected from oxygen, nitrogen, and sulfur, 3- or 5-7-membered saturatedor partially unsaturated monocyclic carbocyclyl, and 3- to 7-memberedsaturated or partially unsaturated monocyclic heterocyclyl having 1-2heteroatoms selected from oxygen, nitrogen, and sulfur; R¹⁴ isoptionally present, and if present and is selected from halogen, —CN,—C(R)═N(R), —C(O)R, —C(O)₂R, —C(O)N(R)₂, —NO₂, —N(R)—N(R)₂, —N(R)C(O)R,—N(R)C(O)₂R, —N(R)C(O)N(R)₂, —N(R)S(O)₂R, —OC(O)R, —OC(O)N(R)₂, —SR,—S(O)R, —S(O)₂R, —S(O)N(R)₂, —S(O)₂N(R)₂, or an optionally substitutedgroup selected from C₃₋₆ aliphatic, phenyl, 5- to 6-membered heteroarylhaving 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur, 3- to7-membered saturated or partially unsaturated monocyclic carbocyclyl,and 3- to 7-membered saturated or partially unsaturated monocyclicheterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, andsulfur; and each R is independently hydrogen, —CN, or an optionallysubstituted group selected from C aliphatic, phenyl, 5- to 6-memberedheteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, andsulfur, 3- to 7-membered saturated or partially unsaturated monocycliccarbocyclyl, and 3- to 7-membered saturated or partially unsaturatedmonocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen,nitrogen, and sulfur; or two R groups on the same carbon or nitrogen aretaken together with their intervening atoms to form a ring selected from3- to 7-membered saturated or partially unsaturated monocyclic ringhaving 0-2 heteroatoms selected from oxygen, nitrogen, and sulfur, and5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen,nitrogen, and sulfur.
 4. The compound of claim 1, wherein L is selectedfrom the group consisting of:

wherein # represents to point of attachment to CyA.
 5. The compound ofclaim 1, wherein the compound is of Formula (II):

or a pharmaceutically acceptable salt thereof, wherein: Cy^(A) isselected from 3- to 7-membered saturated or partially unsaturatedmonocyclic heterocyclyenel having 1-2 heteroatoms selected from oxygen,nitrogen, and sulfur, 5- to 6-membered heteroarylene having 1-4heteroatoms selected from oxygen, nitrogen, and sulfur, 7- to10-membered saturated or partially unsaturated bicyclic heterocyclylenehaving 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur, and7- to 10-membered bicyclic heteroarylene having 1-4 heteroatoms selectedfrom oxygen, nitrogen, and sulfur, wherein Cy^(A) is substituted with0-4 R^(A) groups; each R^(A) is independently selected from halogen,—CN, —C(R)═N(R), —C(O)R, —C(O)₂R, —C(O)N(R)₂, —NO₂, —N(R)—N(R)₂, —N(R)₂,—N(R)C(O)R, —N(R)C(O)₂R, —N(R)C(O)N(R)₂, —N(R)S(O)₂R, —OR, —OC(O)R,—OC(O)N(R)₂, —SR, —S(O)R, —S(O)₂R, —S(O)N(R)₂, —S(O)₂N(R)₂, or anoptionally substituted group selected from C₁₋₆ aliphatic, phenyl, 5- to6-membered heteroaryl having 1-4 heteroatoms selected from oxygen,nitrogen, and sulfur, 3- to 7-membered saturated or partiallyunsaturated monocyclic carbocyclyl, and 3- to 7-membered saturated orpartially unsaturated monocyclic heterocyclyl having 1-2 heteroatomsselected from oxygen, nitrogen, and sulfur; Cy^(B) is selected from 3-to 7-membered saturated or partially unsaturated monocyclic heterocyclylhaving 1-2 heteroatoms selected from oxygen, nitrogen, and sulfur, 5- to6-membered heteroaryl having 1-4 heteroatoms selected from oxygen,nitrogen, and sulfur, 7- to 10-membered saturated or partiallyunsaturated bicyclic heterocyclyl having 1-5 heteroatoms selected fromoxygen, nitrogen, and sulfur, and 7- to 10-membered bicyclic heteroarylhaving 1-5 heteroatoms selected from oxygen, nitrogen, and sulfur,wherein Cy^(B) is substituted with 0-5 R^(B) groups; each R^(B) isindependently selected from halogen, —CN, —C(R)═N(R), —C(O)R, —C(O)₂R,—C(O)N(R)₂, —NO₂, —N(R)—N(R)₂, —N(R)₂, —N(R)C(O)R, —N(R)C(O)₂R,—N(R)C(O)N(R)₂, —N(R)S(O)₂R, —OR, —OC(O)R, —OC(O)N(R)₂, —SR, —S(O)R,—S(O)₂R, —S(O)N(R)₂, —S(O)₂N(R)₂, or an optionally substituted groupselected from C₁₋₆ aliphatic, phenyl, 5- to 6-membered heteroaryl having1-4 heteroatoms selected from oxygen, nitrogen, and sulfur, 3- to7-membered saturated or partially unsaturated monocyclic carbocyclyl,and 3- to 7-membered saturated or partially unsaturated monocyclicheterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, andsulfur; R¹ and R² are independently selected from hydrogen and C₁₋₆aliphatic; R⁶ and R⁷ are independently selected from hydrogen, halogen,—CN, —C(R)═N(R), —C(O)R, —C(O)₂R, —C(O)N(R)₂, —NO₂, —N(R)—N(R)₂, —N(R)₂,—N(R)C(O)R, —N(R)C(O)₂R, —N(R)C(O)N(R)₂, —N(R)S(O)₂R, —OR, —OC(O)R,—OC(O)N(R)₂, —SR, —S(O)R, —S(O)₂R, —S(O)N(R)₂, —S(O)₂N(R)₂, or anoptionally substituted group selected from C₁₋₆ aliphatic, phenyl, 5- to6-membered heteroaryl having 1-4 heteroatoms selected from oxygen,nitrogen, and sulfur, 3- to 7-membered saturated or partiallyunsaturated monocyclic carbocyclyl, and 3- to 7-membered saturated orpartially unsaturated monocyclic heterocyclyl having 1-2 heteroatomsselected from oxygen, nitrogen, and sulfur; and each R is independentlyhydrogen, —CN, or an optionally substituted group selected from C₁₋₆aliphatic, phenyl, 5- to 6-membered heteroaryl having 1-4 heteroatomsselected from oxygen, nitrogen, and sulfur, 3- to 7-membered saturatedor partially unsaturated monocyclic carbocyclyl, and 3- to 7-memberedsaturated or partially unsaturated monocyclic heterocyclyl having 1-2heteroatoms selected from oxygen, nitrogen, and sulfur; or two R groupson the same carbon or nitrogen are taken together with their interveningatoms to form a ring selected from 3- to 7-membered saturated orpartially unsaturated monocyclic ring having 0-2 heteroatoms selectedfrom oxygen, nitrogen, and sulfur, and 5- to 6-membered heteroarylhaving 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur; withthe proviso that the compound is other thanN-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-2-((3-chloroquinolin-6-yl)methyl)isonicotinamide.6. The compound of claim 1, wherein Cy^(A) is selected from 5- to6-membered heteroaryl having 1-4 heteroatoms selected from oxygen,nitrogen, and sulfur, and 7- to 10-membered bicyclic heteroaryl having1-4 heteroatoms selected from oxygen, nitrogen, and sulfur whereinCy^(A) is substituted with 0-4 R^(A) groups.
 7. The compound of claim 1,wherein Cy^(A) is a 5-membered heteroarylene having 1-4 heteroatomsselected from oxygen, nitrogen, and sulfur, wherein Cy^(A) issubstituted with 0-2 R^(A) groups.
 8. The compound of claim 1, whereinCy^(A) is selected from the group consisting of:

wherein * represents to point of attachment to L.
 9. The compound ofclaim 1, wherein the compound is of Formula (III-a) through (III-d):

or a pharmaceutically acceptable salt thereof, wherein: each R^(A) isindependently selected from halogen, —CN, —C(R)═N(R), —C(O)R, —C(O)₂R,—C(O)N(R)₂, —NO₂, —N(R)—N(R)₂, —N(R)₂, —N(R)C(O)R, —N(R)C(O)₂R,—N(R)C(O)N(R)₂, —N(R)S(O)₂R, —OR, —OC(O)R, —OC(O)N(R)₂, —SR, —S(O)R,—S(O)₂R, —S(O)N(R)₂, —S(O)₂N(R)₂, or an optionally substituted groupselected from C₁₋₆ aliphatic, phenyl, 5- to 6-membered heteroaryl having1-4 heteroatoms selected from oxygen, nitrogen, and sulfur, 3- to7-membered saturated or partially unsaturated monocyclic carbocyclyl,and 3- to 7-membered saturated or partially unsaturated monocyclicheterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, andsulfur; Cy^(B) is selected from 3- to 7-membered saturated or partiallyunsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected fromoxygen, nitrogen, and sulfur, 5- to 6-membered heteroaryl having 1-4heteroatoms selected from oxygen, nitrogen, and sulfur, 7- to10-membered saturated or partially unsaturated bicyclic heterocyclylhaving 1-5 heteroatoms selected from oxygen, nitrogen, and sulfur, and7- to 10-membered bicyclic heteroaryl having 1-5 heteroatoms selectedfrom oxygen, nitrogen, and sulfur, wherein Cy^(B) is substituted with0-5 R^(B) groups; each R^(B) is independently selected from halogen,—CN, —C(R)═N(R), —C(O)R, —C(O)₂R, —C(O)N(R)₂, —NO₂, —N(R)—N(R)₂, —N(R)₂,—N(R)C(O)R, —N(R)C(O)₂R, —N(R)C(O)N(R)₂, —N(R)S(O)₂R, —OR, —OC(O)R,—OC(O)N(R)₂, —SR, —S(O)R, —S(O)₂R, —S(O)N(R)₂, —S(O)₂N(R)₂, or anoptionally substituted group selected from C₁₋₆ aliphatic, phenyl, 5- to6-membered heteroaryl having 1-4 heteroatoms selected from oxygen,nitrogen, and sulfur, 3- to 7-membered saturated or partiallyunsaturated monocyclic carbocyclyl, and 3- to 7-membered saturated orpartially unsaturated monocyclic heterocyclyl having 1-2 heteroatomsselected from oxygen, nitrogen, and sulfur; R¹ and R² are independentlyselected from hydrogen and C₁₋₆ aliphatic; R⁶ and R⁷ are independentlyselected from hydrogen, halogen, —CN, —C(R)═N(R), —C(O)R, —C(O)₂R,—C(O)N(R)₂, —NO₂, —N(R)—N(R)₂, —N(R)₂, —N(R)C(O)R, —N(R)C(O)₂R,—N(R)C(O)N(R)₂, —N(R)S(O)₂R, —OR, —OC(O)R, —OC(O)N(R)₂, —SR, —S(O)R,—S(O)₂R, —S(O)N(R)₂, —S(O)₂N(R)₂, or an optionally substituted groupselected from C₁₋₆ aliphatic, phenyl, 5- to 6-membered heteroaryl having1-4 heteroatoms selected from oxygen, nitrogen, and sulfur, 3- to7-membered saturated or partially unsaturated monocyclic carbocyclyl,and 3- to 7-membered saturated or partially unsaturated monocyclicheterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, andsulfur; and each R is independently hydrogen, —CN, or an optionallysubstituted group selected from C₁₋₆ aliphatic, phenyl, 5- to 6-memberedheteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, andsulfur, 3- to 7-membered saturated or partially unsaturated monocycliccarbocyclyl, and 3- to 7-membered saturated or partially unsaturatedmonocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen,nitrogen, and sulfur; or two R groups on the same carbon or nitrogen aretaken together with their intervening atoms to form a ring selected from3- to 7-membered saturated or partially unsaturated monocyclic ringhaving 0-2 heteroatoms selected from oxygen, nitrogen, and sulfur, and5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen,nitrogen, and sulfur.
 10. The compound of claim 1, wherein Cy^(B) is a7- to 10-membered bicyclic heteroaryl having 1-5 heteroatoms selectedfrom oxygen, nitrogen, and sulfur, wherein Cy^(B) is substituted with0-5 R^(B) groups.
 11. The compound of claim 1, wherein Cy^(B) is

wherein: W¹, W², W³, and W⁴ are independently selected from carbon andnitrogen; R¹⁰, R¹¹, R¹², R¹³, and R¹⁴ are each optionally present whenattached to a carbon atom, and if present correspond to an occurrence ofR^(B) independently selected from halogen, —CN, —C(R)═N(R), —C(O)R,—C(O)₂R, —C(O)N(R)₂, —NO₂, —N(R)—N(R)₂, —N(R)₂, —N(R)C(O)R, —N(R)C(O)₂R,—N(R)C(O)N(R)₂, —N(R)S(O)₂R, —OR, —OC(O)R, —OC(O)N(R)₂, —SR, —S(O)R,—S(O)₂R, —S(O)N(R)₂, —S(O)₂N(R)₂, or an optionally substituted groupselected from C₁₋₆ aliphatic, phenyl, 5- to 6-membered heteroaryl having1-4 heteroatoms selected from oxygen, nitrogen, and sulfur, 3- to7-membered saturated or partially unsaturated monocyclic carbocyclyl,and 3- to 7-membered saturated or partially unsaturated monocyclicheterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, andsulfur; and each R is independently hydrogen, —CN, or an optionallysubstituted group selected from C-aliphatic, phenyl, 5- to 6-memberedheteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, andsulfur, 3- to 7-membered saturated or partially unsaturated monocycliccarbocyclyl, and 3- to 7-membered saturated or partially unsaturatedmonocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen,nitrogen, and sulfur; or two R groups on the same carbon or nitrogen aretaken together with their intervening atoms to form a ring selected from3- to 7-membered saturated or partially unsaturated monocyclic ringhaving 0-2 heteroatoms selected from oxygen, nitrogen, and sulfur, and5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen,nitrogen, and sulfur.
 12. The compound of claim 1, wherein Cy^(B) isselected from the group consisting of:


13. The compound of claim 1, wherein Cy^(B) is

wherein: W² is selected from carbon, nitrogen, oxygen, and sulfur; W¹,W³, and W⁴ are independently selected from carbon and nitrogen; R¹⁰,R¹¹, R¹², R¹³, and R¹⁴ are each optionally present when attached to acarbon atom, and if present correspond to an occurrence of R^(B)independently selected from halogen, —CN, —C(R)═N(R), —C(O)R, —C(O)₂R,—C(O)N(R)₂, —NO₂, —N(R)—N(R)₂, —N(R)₂, —N(R)C(O)R, —N(R)C(O)₂R,—N(R)C(O)N(R)₂, —N(R)S(O)₂R, —OR, —OC(O)R, —OC(O)N(R)₂, —SR, —S(O)R,—S(O)₂R, —S(O)N(R)₂, —S(O)₂N(R)₂, or an optionally substituted groupselected from C₁₋₆ aliphatic, phenyl, 5- to 6-membered heteroaryl having1-4 heteroatoms selected from oxygen, nitrogen, and sulfur, 3- to7-membered saturated or partially unsaturated monocyclic carbocyclyl,and 3- to 7-membered saturated or partially unsaturated monocyclicheterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, andsulfur; and each R is independently hydrogen, —CN, or an optionallysubstituted group selected from C-aliphatic, phenyl, 5- to 6-memberedheteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, andsulfur, 3- to 7-membered saturated or partially unsaturated monocycliccarbocyclyl, and 3- to 7-membered saturated or partially unsaturatedmonocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen,nitrogen, and sulfur; or two R groups on the same carbon or nitrogen aretaken together with their intervening atoms to form a ring selected from3- to 7-membered saturated or partially unsaturated monocyclic ringhaving 0-2 heteroatoms selected from oxygen, nitrogen, and sulfur, and5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen,nitrogen, and sulfur.
 14. The compound of claim 1, wherein Cy^(B) isselected from the group consisting of:


15. The compound of claim 1, wherein R⁵, R⁶, R⁷, R⁸, and R⁹ areindependently selected from hydrogen, halogen, —CN, —N(R)₂, —OR, or anoptionally substituted group selected from C₁₋₆ aliphatic, 3- to7-membered saturated or partially unsaturated monocyclic carbocyclyl,wherein each R is independently hydrogen or C₁₋₆ aliphatic.
 16. Thecompound of claim 1, wherein R is selected from hydrogen and halogen.17. The compound of claim 1, wherein the compound is any one ofcompounds I-1 through I-303 as shown in Table 1, or a pharmaceuticallyacceptable salt thereof.
 18. A pharmaceutical composition comprising thecompound of claim 1 and further comprising a pharmaceutically acceptableexcipient.
 19. A method of treating a plasma kallikrein-mediated diseaseor disorder using a compound of claim
 1. 20. A method of treatinghereditary angioedema or diabetic macular edema comprising administeringto a patient in need thereof a compound of claim
 1. 21. A pharmaceuticalcomposition comprising the compound of claim 17 or a pharmaceuticallyacceptable salt thereof, and further comprising a pharmaceuticallyacceptable excipient.